| 1. |
- Albertsson, Anna-Maj, et al.
(author)
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The immune response after hypoxia-ischemia in a mouse model of preterm brain injury.
- 2014
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In: Journal of neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 11:1
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Journal article (peer-reviewed)abstract
- BackgroundPreterm brain injury consists primarily of periventricular leukomalacia accompanied by elements of gray-matter injury, and these injuries are associated with cerebral palsy and cognitive impairments. Inflammation is believed to be an important contributing factor to these injuries. The aim of this study was to examine the immune response in a postnatal day (PND) 5 mouse model of preterm brain injury induced by hypoxia-ischemia (HI) that is characterized by focal white and gray-matter injury.MethodsC57Bl/6 mice at PND 5 were subjected to unilateral HI induced by left carotid artery ligation and subsequent exposure to 10% O2 for 50 minutes, 70 minutes, or 80 minutes. At seven days post-HI, the white/gray-matter injury was examined. The immune responses in the brain after HI were examined at different time points after HI using RT-PCR and immunohistochemical staining.ResultsHI for 70 minutes in PND 5 mice induced local white-matter injury with focal cortical injury and hippocampal atrophy, features that are similar to those seen in preterm brain injury in human infants. HI for 50 minutes resulted in a small percentage of animals being injured, and HI for 80 minutes produced extensive infarction in multiple brain areas. Various immune responses, including changes in transcription factors and cytokines that are associated with a T-helper (Th)1/Th17-type response, an increased number of CD4+ T-cells, and elevated levels of triggering receptor expressed on myeloid cells 2 (TREM-2) and its adaptor protein DNAX activation protein of 12 kDa (DAP12) were observed using the HI 70 minute preterm brain injury model.ConclusionsWe have established a reproducible model of HI in PND 5 mice that produces consistent local white/gray-matter brain damage that is relevant to preterm brain injury in human infants. This model provides a useful tool for studying preterm brain injury. Both innate and adaptive immune responses are observed after HI, and these show a strong pro-inflammatory Th1/Th17-type bias. Such findings provide a critical foundation for future studies on the mechanism of preterm brain injury and suggest that blocking the Th1/Th17-type immune response might provide neuroprotection after preterm brain injury.
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| 2. |
- Albertsson, Anna-Maj, et al.
(author)
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γδ T cells contribute to injury in the developing brain.
- 2018
-
In: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 188:3, s. 757-767
-
Journal article (peer-reviewed)abstract
- Brain injury in premature infants, especially periventricular leukomalacia, is an important cause of neurological disabilities. Inflammation contributes to the development of perinatal brain injury, but the essential mediators leading to brain injury in early life remain largely unknown. Neonates have reduced capacity for mounting conventional αβT-cell responses. However γδT-cells are already functionally competent during early development and are important in early life immunity. We investigated the potential contribution of γδT-cells to preterm brain injury by using postmortem brains from human preterm infants with periventricular leukomalacia and two animal models of preterm brain injury-the hypoxic-ischemic mouse model and a fetal sheep asphyxia model. Large numbers of γδT-cells were observed in the brains of mice, sheep, and postmortem preterm infants after injury, and depletion of γδT-cells provided protection in the mouse model. The common γδT-cell associated cytokines interferon-γ and interleukin (IL)-17A were not detectable in the brain. Although there were increased mRNA levels of Il17f and Il22 in the mouse brains after injury, neither IL-17F nor IL-22 cytokines contributed to preterm brain injury. These findings highlight unique features of injury in the developing brain where, unlike injury in the mature brain, γδT-cells function as important initiators of injury independently of common γδT-cell associated cytokines. This new finding will help to identify therapeutic targets for preventing or treating preterm infants with brain injury.
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| 3. |
- Albutti, A., et al.
(author)
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Type II NKT cell agonist, sulfatide, is an effective adjuvant for oral heat-killed cholera vaccines
- 2021
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In: Vaccines. - : MDPI AG. - 2076-393X. ; 9:6
-
Journal article (peer-reviewed)abstract
- Oral vaccination has the potential to offer a safer and more efficacious approach for protection against enteric pathogens than injection-based approaches, especially in developing countries. One key advantage is the potential to induce intestinal immune responses in addition to systemic immunity. In general, antigen delivery via the oral route triggers weak immune responses or immunological tolerance. The effectiveness of oral vaccination can be improved by co-administering adjuvants. However, a major challenge is the absence of potent and safe oral adjuvants for clinical application. Here, the Type II NKT cell activator sulfatide is shown for the first time to be an effective oral adjuvant for Vibrio cholerae vaccine antigens in a mouse model. Specifically, administration of sulfatide with the oral cholera vaccine Dukoral® resulted in enhancement of intestinal antigen-specific IgA in addition to Th1 and Th17 immune responses. In summary, sulfatide is a promising adjuvant for inclusion in an oral cholera vaccine and our data further support the potential of adjuvants targeting NKT cells in new vaccine strategies. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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| 4. |
- Assarsson, Erika, et al.
(author)
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Severe defect in thymic development in an insertional mutant mouse model.
- 2007
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In: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 178:8, s. 5018-5027
-
Journal article (peer-reviewed)abstract
- Transgenic mice were generated expressing NK1.1, an NK cell-associated receptor, under control of the human CD2 promoter. Unexpectedly, one of the founder lines, Tg66, showed a marked defect in thymic development characterized by disorganized architecture and small size. Mapping of the transgene insertion by fluorescence in situ hybridization revealed integration in chromosome 2, band G. Already from postnatal day 3, the thymic architecture was disturbed with a preferential loss of cortical thymic epithelial cells, a feature that became more pronounced over time. Compared with wild-type mice, total thymic cell numbers decreased dramatically between 10 and 20 days of age. Thymocytes isolated from adult Tg66 mice were predominantly immature double-negative cells, indicating a block in thymic development at an early stage of differentiation. Consequently, Tg66 mice had reduced numbers of peripheral CD4(+) and CD8(+) T cells. Bone marrow from Tg66 mice readily reconstituted thymi of irradiated wild-type as well as RAG-deficient mice. This indicates that the primary defect in Tg66 mice resided in nonhemopoietic stromal cells of the thymus. The phenotype is observed in mice heterozygous for the insertion and does not resemble any known mutations affecting thymic development. Preliminary studies in mice homozygous for transgene insertion reveal a more accelerated and pronounced phenotype suggesting a semidominant effect. The Tg66 mice may serve as a useful model to identify genes regulating thymic epithelial cell differentiation, thymic development, and function.
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| 5. |
- Blomqvist, Maria K., 1975, et al.
(author)
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Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells.
- 2009
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In: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 39:7, s. 1726-35
-
Journal article (peer-reviewed)abstract
- The glycosphingolipid sulfatide (SO(3)-3Galbeta1Cer) is a demonstrated ligand for a subset of CD1d-restricted NKT cells, which could regulate experimental autoimmune encephalomyelitis, a murine model for multiple sclerosis, as well as tumor immunity and experimental hepatitis. Native sulfatide is a mixture of sulfatide isoforms, i.e. sulfatide molecules with different long-chain bases and fatty acid chain lengths and saturation. Here, we demonstrate that sulfatide-specific CD1d-restricted murine NKT hybridomas recognized several different sulfatide isoforms. These included the physiologically relevant isoforms C24:1 and C24:0, major constituents of the myelin sheet of the nervous system, and C16:0, prominent in the pancreatic islet beta-cells. The most potent sulfatide isoform was lysosulfatide (lacking a fatty acid). Shortened fatty acid chain length (C24:1 versus C18:1), or saturation of the long fatty acid (C24:0), resulted in reduced stimulatory capacity, and fatty acid hydroxylation abolished the response. Moreover, sulfatide was not responsible for the natural autoreactivity toward splenocytes by XV19 T hybridoma cells. Our results reveal a promiscuity in the recognition of sulfatide isoforms by a CD1d-restricted NKT-cell clone, and suggest that sulfatide, a major component of the myelin sheet and pancreatic beta-cells, is one of several natural ligands for type II CD1d-restricted NKT cells.
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| 6. |
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| 7. |
- Camponeschi, Alessandro, et al.
(author)
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Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity.
- 2019
-
In: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 10
-
Journal article (peer-reviewed)abstract
- Immunological memory ensures life-long protection against previously encountered pathogens, and in mice and humans the spleen is an important reservoir for long-lived memory B cells (MBCs). It is well-established that integrins play several crucial roles in lymphocyte survival and trafficking, but their involvement in the retention of MBCs in secondary lymphoid organs, and differences between B cell subsets in their adhesion capacity to ICAM-1 and/or VCAM-1 have not yet been confirmed. Here, we use an autoimmune mouse model, where MBCs are abundant, to show that the highest levels of LFA-1 and VLA-4 amongst B cells are found on MBCs. In vivo blockade of VLA-4 alone or in combination with LFA-1, but not LFA-1 alone, causes a release of MBCs from the spleen into the blood stream. In humans, we find that in peripheral blood, spleens, and tonsils from healthy donors the highest expression levels of the integrins LFA-1 and VLA-4 are also found on MBCs. Consistent with this, we found MBCs to have a higher capacity to adhere to ICAM-1 and VCAM-1 than naïve B cells. In patients with the autoimmune disease rheumatoid arthritis, it is the MBCs that have the highest levels of LFA-1 and VLA-4; moreover, compared with healthy donors, naïve B and MBCs of patients receiving anti-TNF medication have enhanced levels of the active form of LFA-1. Commensurate levels of the active αL subunit can be induced on B cells from healthy donors by exposure to the integrin ligands. Thus, our findings establish the selective use of the integrins LFA-1 and VLA-4 in the localization and adhesion of MBCs in both mice and humans.
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| 8. |
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| 9. |
- Cardell, Susanna, 1959
(author)
-
The natural killer T lymphocyte: a player in the complex regulation of autoimmune diabetes in non-obese diabetic mice.
- 2006
-
In: Clinical and experimental immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 143:2, s. 194-202
-
Research review (peer-reviewed)abstract
- Manipulation of the immune response to specifically prevent autoaggression requires an understanding of the complex interactions that occur during the pathogenesis of autoimmunity. Much attention has been paid to conventional T lymphocytes recognizing peptide antigens presented by classical major histocompatibility complex (MHC) class I and II molecules, as key players in the destructive autoreactive process. A pivotal role for different types of regulatory T lymphocytes in modulating the development of disease is also well established. Lately, CD1d-restricted natural killer T (NKT) lymphocytes have been the subject of intense investigation because of their ability to regulate a diversity of immune responses. The non-classical antigen presenting molecule CD1d presents lipids and glycolipids to this highly specialized subset of T lymphocytes found in both humans and mice. From experimental models of autoimmunity, evidence is accumulating that NKT cells can protect from disease. One of the best studied is the murine type 1 diabetes model, the non-obese diabetic (NOD) mouse. While the NKT cell population was first recognized to be deficient in NOD mice, augmenting NKT cell activity has been shown to suppress the development of autoimmune disease in this strain. The mechanism by which CD1d-restricted T cells exert this function is still described incompletely, but investigations in NOD mice are starting to unravel specific effects of NKT cell regulation. This review focuses on the role of CD1d-restricted NKT cells in the control of autoimmune diabetes.
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| 10. |
- Cardell, Susanna, 1959, et al.
(author)
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Tolerization of diabetogenic CD4+T cells by intranasal treatment with CTA1R7K-DD containing specific peptide through the induction of FoxP3+Treg cells
- 2012
-
In: Journal of Immunology. - 0022-1767. ; 188
-
Conference paper (other academic/artistic)abstract
- Type I diabetes (T1D) results from immune destruction of insulin producing β-cells in the pancreas islets. Diabetogenic CD4+ T cells are key cells in the autoimmune process. To achieve tolerization of diabetogenic CD4+ T cells would therefore be an important advancement in the development of treatments of T1D. We previously described that a mutated (R7K), enzyme killed, form of the cholera toxin A1 subunit based adjuvant CTA1-DD induces specific tolerance rather than enhancement of immunity. Intranasal (i n) treatment with CTA1R7K-DD containing a type II collagen peptide reduced in vitro recall responses to the peptide, and moreover, ameliorated collagen induced arthritis in mice. Here, we use CTA1R7K-DD to investigate tolerization of diabetogenic CD4+ T cells of the non-obese diabetic (NOD) mouse, exploring diabetogenic TCR transgenic BDC2.5 CD4+ T cells. I n treatment of BDC2.5 NOD mice with CTA1R7K-DD containing a peptide specific for the BDC2.5 TCR reduced proliferation and IFN-{gamma} production to in vitro peptide stimulation. Transfer of CD4+ BDC2.5 T cells to NOD.scid mice results in T1D development in 80-100% of recipient mice. In contrast, recipients of cells from BDC2.5 NOD mice treated with the CTA1R7K-DD peptide construct remained healthy. The i n treatment resulted in systemic increase in the frequency of CD4+ BDC2.5 transgenic T cells expressing FoxP3, suggesting that CTA1R7K-peptide-DD induces specific CD4+ Treg cells preventing T1D development.
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| 11. |
- Clark, K., et al.
(author)
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Structure-Function Implications of the Ability of Monoclonal Antibodies Against alpha-Galactosylceramide-CD1d Complex to Recognize beta-Mannosylceramide Presentation by CD1d
- 2019
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
-
Journal article (peer-reviewed)abstract
- iNKT cells are CD1d-restricted T cells recognizing lipid antigens. The prototypic iNKT cell-agonist alpha-galactosylceramide (alpha-GalCer) alongside compounds with similar structures induces robust proliferation and cytokine production of iNKT cells and protects against cancer in vivo. Monoclonal antibodies (mAbs) that detect CD1d-alpha-GalCer complexes have provided critical information for understanding of antigen presentation of iNKT cell agonists. Although most iNKT cell agonists with antitumor properties are alpha-linked glycosphingolipids that can be detected by anti-CD1d-alpha-GalCer mAbs, beta-ManCer, a glycolipid with a beta-linkage, induces strong antitumor immunity via mechanisms distinct from those of alpha-GalCer. In this study, we unexpectedly discovered that anti-CD1d-alpha-GalCer mAbs directly recognized beta-ManCer-CD1d complexes and could inhibit beta-ManCer stimulation of iNKT cells. The binding of anti-CD1d-alpha-GalCer mAb with beta-ManCer-CD1d complexes was also confirmed by plasmon resonance and could not be explained by alpha-anomer contamination. The binding of anti-CD1d-alpha-GalCer mAb was also observed with CD1d loaded with another beta-linked glycosylceramide, beta-GalCer (C26:0). Detection with anti-CD1d-alpha-GalCer mAbs indicates that the interface of the beta-ManCer-CD1d complex exposed to the iNKT cell TCR can assume a structure like that of CD1d-alpha-GalCer, despite its disparate carbohydrate structure. These results suggest that certain beta-linked monoglycosylceramides can assume a structural display similar to that of CD1d-alpha-GalCer and that the data based on anti-CD1d-alpha-GalCer binding should be interpreted with caution.
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| 12. |
- Cossarizza, A., et al.
(author)
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Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
- 2019
-
In: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 49:10, s. 1457-1973
-
Journal article (peer-reviewed)abstract
- These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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| 13. |
- Fernández-Santoscoy, Maria, et al.
(author)
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The Gut Microbiota Reduces Colonization of the Mesenteric Lymph Nodes and IL-12-Independent IFN-gamma Production During Salmonella Infection
- 2015
-
In: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media SA. - 2235-2988. ; 5
-
Journal article (peer-reviewed)abstract
- The intestinal commensal microbiota is essential for many host physiological processes, but its impact on infectious diseases is poorly understood. Here we investigate the influence of the gut microbiota during oral Salmonella infection. We report a higher bacterial burden in mesenteric lymph nodes (MLN) of intragastrically infected germ-free (GF) mice compared to conventionally-raised (CONV-R) animals, despite similar inflammatory phagocyte recruitment. Salmonella penetration into the lamina propria of the small intestine and splenic bacterial burden were not altered in the absence of the microbiota. Intragastrically infected GF mice also displayed a higher frequency of IFN-gamma-producing NK, NKT, CD4(+), and CD8(+) T cells in the MLN despite IL-12 levels similar to infected CONV-R mice. However, infecting mice intraperitoneally abrogated the difference in MLN bacterial load and IFN-gamma-producing cells observed in intragastrically-infected animals. Moreover, mice treated with antibiotics (ABX) and intragastrically infected with Salmonella had a greater bacterial burden and frequency of IFN-gamma-producing cells in the MLN. In ABX mice the number of Salmonella correlated with the frequency of IFN-gamma-producing lymphocytes in the MLN, while no such correlation was observed in the MLN of infected GF mice. Overall, the data show that the lack of the microbiota influences pathogen colonization of the MLN, and the increased IFN-gamma in the MLN of infected GF mice is not only due to the absence of commensals at the time of infection but the lack of immune signals provided by the microbiota from birth.
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| 14. |
- Fransén-Pettersson, Nina, et al.
(author)
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A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis
- 2016
-
In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:7
-
Journal article (peer-reviewed)abstract
- Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.
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| 15. |
- Grimsholm, Ola, 1979, et al.
(author)
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Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding V(H)81X-expressing B cells
- 2015
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Journal article (peer-reviewed)abstract
- Random recombination of antibody heavy- and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive V(H)81X from both pools.
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| 16. |
- Johansson, Gustav, et al.
(author)
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Ultrasensitive DNA Immune Repertoire Sequencing Using Unique Molecular Identifiers.
- 2020
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In: Clinical chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 66:9, s. 1228-1237
-
Journal article (peer-reviewed)abstract
- Immune repertoire sequencing of the T-cell receptor can identify clonotypes that have expanded as a result of antigen recognition or hematological malignancies. However, current sequencing protocols display limitations with nonuniform amplification and polymerase-induced errors during sequencing. Here, we developed a sequencing method that overcame these issues and applied it to γδ T cells, a cell type that plays a unique role in immunity, autoimmunity, homeostasis of intestine, skin, adipose tissue, and cancer biology.The ultrasensitive immune repertoire sequencing method used PCR-introduced unique molecular identifiers. We constructed a 32-panel assay that captured the full diversity of the recombined T-cell receptor delta loci in γδ T cells. The protocol was validated on synthetic reference molecules and blood samples of healthy individuals.The 32-panel assay displayed wide dynamic range, high reproducibility, and analytical sensitivity with single-nucleotide resolution. The method corrected for sequencing-depended quantification bias and polymerase-induced errors and could be applied to both enriched and nonenriched cells. Healthy donors displayed oligoclonal expansion of γδ T cells and similar frequencies of clonotypes were detected in both enrichment and nonenriched samples.Ultrasensitive immune repertoire sequencing strategy enables quantification of individual and specific clonotypes in a background that can be applied to clinical as well as basic application areas. Our approach is simple, flexible, and can easily be implemented in any molecular laboratory.
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| 17. |
- Kadri, Nadir, 1977, et al.
(author)
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CD4(+) type II NKT cells mediate ICOS and programmed death-1-dependent regulation of type 1 diabetes.
- 2012
-
In: Journal of immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 188:7, s. 3138-49
-
Journal article (peer-reviewed)abstract
- Type 1 diabetes (T1D) is a chronic autoimmune disease that results from T cell-mediated destruction of pancreatic β cells. CD1d-restricted NKT lymphocytes have the ability to regulate immunity, including autoimmunity. We previously demonstrated that CD1d-restricted type II NKT cells, which carry diverse TCRs, prevented T1D in the NOD mouse model for the human disease. In this study, we show that CD4(+) 24αβ type II NKT cells, but not CD4/CD8 double-negative NKT cells, were sufficient to downregulate diabetogenic CD4(+) BDC2.5 NOD T cells in adoptive transfer experiments. CD4(+) 24αβ NKT cells exhibited a memory phenotype including high ICOS expression, increased cytokine production, and limited display of NK cell markers, compared with double-negative 24αβ NKT cells. Blocking of ICOS or the programmed death-1/programmed death ligand 1 pathway was shown to abolish the regulation that occurred in the pancreas draining lymph nodes. To our knowledge, these results provide for the first time cellular and molecular information on how type II CD1d-restricted NKT cells regulate T1D.
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| 18. |
- Kadri, Nadir, 1977, et al.
(author)
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Type II natural killer T cells: a new target for immunomodulation?
- 2008
-
In: Expert Review of Clinical Immunology. - 1744-666X. ; 4, s. 615-627
-
Research review (peer-reviewed)abstract
- Natural killer (NK) T lymphocytes are potent immuno regulatory cells that can regulate diverse immune responses. NKT cells display a low degree of inherent autoreactivity, and are activated by endogenous or pathogen specific glycolipids presented on the cluster of differentiation (CD)1d molecule. Recent studies have focused attention to type II NKT cells, which in contrast to type I NKT cells display a diverse T cell receptor repertoire. Type II NKT cells in mice and humans demonstrate a unique regulatory role in autoimmunity, tumor immunity and infections. Immuno therapy targeting type II NKT cells in experimental models prevents autoimmune disease and protects mice from experimental hepatitis. Current efforts aim to reveal the underlying regulatory mechanisms of type II NKT cells in mice and humans, and to identify the parameters that guide their activation, working towards the development of selective immuno therapies targeting type II NKT cells in autoimmunity and other immune mediated diseases.
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| 19. |
- Korpos, Eva, et al.
(author)
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The Peri-islet Basement Membrane, a Barrier to Infiltrating Leukocytes in Type 1 Diabetes in Mouse and Human.
- 2013
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In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:2, s. 531-42
-
Journal article (peer-reviewed)abstract
- We provide the first comprehensive analysis of the extracellular matrix (ECM) composition of peri-islet capsules, composed of the peri-islet basement membrane (BM) and subjacent interstitial matrix (IM), in development of type 1 diabetes in NOD mice and in human type 1 diabetes. Our data demonstrate global loss of peri-islet BM and IM components only at sites of leukocyte infiltration into the islet. Stereological analyses reveal a correlation between incidence of insulitis and the number of islets showing loss of peri-islet BM versus islets with intact BMs, suggesting that leukocyte penetration of the peri-islet BM is a critical step. Protease- and protease inhibitor-specific microarray analyses (CLIP-CHIP) of laser-dissected leukocyte infiltrated and noninfiltrated pancreatic islets and confirmatory quantitative real time PCR and protein analyses identified cathepsin S, W, and C activity at sites of leukocyte penetration of the peri-islet BM in association with a macrophage subpopulation in NOD mice and human type 1 diabetic samples and, hence, potentially a novel therapeutic target specifically acting at the islet penetration stage. Interestingly, the peri-islet BM and underlying IM are reconstituted once inflammation subsides, indicating that the peri-islet BM-producing cells are not lost due to the inflammation, which has important ramifications to islet transplantation studies.
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| 20. |
- Kwiecinski, Jakub, 1985, et al.
(author)
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Sulfatide attenuates experimental Staphylococcal aureus sepsis through a CD1d-dependent pathway.
- 2013
-
In: Infection and immunity. - 1098-5522. ; 81:4, s. 1114-1120
-
Journal article (peer-reviewed)abstract
- Natural killer T (NKT) lymphocytes are implicated in the early response to microbial infection. Further, sulfatide, a myelin self-glycosphingolipid, activates a type II NKT cell subset, and can modulate disease in murine models. We examined the role of NKT cells and the effect of sulfatide treatment in a murine model of Staphylococcus aureus sepsis. Lack of CD1d-restricted NKT cells did not alter survival after a lethal inoculum of S. aureus. In contrast, sulfatide treatment significantly improved the survival rate of mice with S. aureus sepsis, accompanied by decreased levels of TNF-α and IL-6 in the blood. The protective effect of sulfatide treatment depended on CD1d, but not on type I NKT cells, suggesting that activation of type II NKT cells by sulfatide has beneficial effects on the outcome of S. aureus sepsis in this model.
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| 21. |
- Lebrero-Fernandez, Cristina, et al.
(author)
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Altered expression of Butyrophilin (BTN) and BTN-like (BTNL) genes in intestinal inflammation and colon cancer
- 2016
-
In: Immunity Inflammation and Disease. - : Wiley. - 2050-4527. ; 4:2, s. 191-200
-
Journal article (peer-reviewed)abstract
- Several Butyrophilin (BTN) and Btn-like (BTNL) molecules control T lymphocyte responses, and are genetically associated with inflammatory disorders and cancer. In this study, we present a comprehensive expression analysis of human and murine BTN and BTNL genes in conditions associated with intestinal inflammation and cancer. Using real-time PCR, expression of human BTN and BTNL genes was analyzed in samples from patients with ulcerative colitis, irritable bowel syndrome, and colon tumors. Expression of murine Btn and Btnl genes was examined in mouse models of spontaneous colitis (Muc2(-/-)) and intestinal tumorigenesis (Apc(Min/+)). Our analysis indicates a strong association of several of the human genes with ulcerative colitis and colon cancer; while especially BTN1A1, BTN2A2, BTN3A3, and BTNL8 were significantly altered in inflammation, colonic tumors exhibited significantly decreased levels of BTNL2, BTNL3, BTNL8, and BTNL9 as compared to unaffected tissue. Colonic inflammation in Muc2(-/-) mice significantly down-regulated the expression of particularly Btnl1, Btnl4, and Btnl6 mRNA, and intestinal polyps derived from Apc(Min/+) mice displayed altered levels of Btn1a1, Btn2a2, and Btnl1 transcripts. Thus, our data present an association of BTN and BTNL genes with intestinal inflammation and cancer and represent a valuable resource for further studies of this gene family.
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| 22. |
- Liao, Chia-Min, et al.
(author)
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Dysregulation of CD1d-restricted type II natural killer T cells leads to spontaneous development of colitis in mice.
- 2012
-
In: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 142:2
-
Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: CD1d-restricted natural killer (NK) T cells are a subset of immunoregulatory T cells that comprise type I (express the semi-invariant T-cell receptor [TCR] and can be detected using the α-galactosylceramide/CD1d tetramer) and type II (express diverse TCRs and cannot be directly identified). Studies in mouse models of inflammatory bowel disease revealed a complex role for type I NKT cells in the development of colitis. Type II NKT cells have been associated with intestinal inflammation in patients with ulcerative colitis. METHODS: To investigate whether dysregulation of type II NKT cells, caused by increased expression of CD1d, can contribute to colitis, we generated transgenic mice that express high levels of CD1d and a TCR from an autoreactive, type II NKT cell (CD1dTg/24αβTg mice). RESULTS: CD1dTg/24αβTg mice had reduced numbers of 24αβ T cells compared with 24αβTg mice, indicating that negative selection increases among type II NKT cells engaged by abundant self-antigen. The residual 24αβ T cells in CD1dTg/24αβTg mice had an altered surface phenotype and acquired a cytokine profile distinct from that of equivalent cells in 24αβTg mice. Interestingly, CD1dTg/24αβTg mice spontaneously developed colitis; adoptive transfer experiments confirmed that type II NKT cells that develop in the context of increased CD1d expression are pathogenic. CONCLUSIONS: Aberrant type II NKT cell responses directly contribute to intestinal inflammation in mice, indicating the importance of CD1d expression levels in the development and regulation of type II NKT cells.
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| 23. |
- Lokmic, Zerina, et al.
(author)
-
The extracellular matrix of the spleen as a potential organizer of immune cell compartments.
- 2008
-
In: Seminars in immunology. - : Elsevier BV. - 1044-5323. ; 20:1, s. 4-13
-
Research review (peer-reviewed)abstract
- Until recently little information was available on the molecular details of the extracellular matrix (ECM) of secondary lymphoid tissues. There is now growing evidence that these ECMs are unique structures, combining characteristics of basement membranes and interstitial or fibrillar matrices, resulting in scaffolds that are strong and highly flexible and, in certain secondary lymphoid compartments, also forming conduit networks for rapid fluid transport. This review will address the structural characteristics of the ECM of the murine spleen and its potential role as an organizer of immune cell compartments, with reference to the lymph node where relevant.
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| 24. |
- Micallef, Peter, 1988, et al.
(author)
-
C1QTNF3 is Upregulated During Subcutaneous Adipose Tissue Remodeling and Stimulates Macrophage Chemotaxis and M1-Like Polarization
- 2022
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
-
Journal article (peer-reviewed)abstract
- The adipose tissue undergoes substantial tissue remodeling during weight gain-induced expansion as well as in response to the mechanical and immunological stresses from a growing tumor. We identified the C1q/TNF-related protein family member C1qtnf3 as one of the most upregulated genes that encode secreted proteins in tumor-associated inguinal adipose tissue - especially in high fat diet-induced obese mice that displayed 3-fold larger tumors than their lean controls. Interestingly, inguinal adipose tissue C1qtnf3 was co-regulated with several macrophage markers and chemokines and was primarily expressed in fibroblasts while only low levels were detected in adipocytes and macrophages. Administration of C1QTNF3 neutralizing antibodies inhibited macrophage accumulation in tumor-associated inguinal adipose tissue while tumor growth was unaffected. In line with this finding, C1QTNF3 exerted chemotactic actions on both M1- and M2-polarized macrophages in vitro. Moreover, C1QTNF3 treatment of M2-type macrophages stimulated the ERK and Akt pathway associated with increased M1-like polarization as judged by increased expression of M1-macrophage markers, increased production of nitric oxide, reduced oxygen consumption and increased glycolysis. Based on these results, we propose that macrophages are recruited to adipose tissue sites with increased C1QTNF3 production. However, the impact of the immunomodulatory effects of C1QTNF3 in adipose tissue remodeling warrants future investigations.
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| 25. |
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| 26. |
- Nilton, Anna, et al.
(author)
-
Zinc Finger Protein 148 Is Dispensable for Primitive and Definitive Hematopoiesis in Mice
- 2013
-
In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
-
Journal article (peer-reviewed)abstract
- Hematopoiesis is regulated by transcription factors that induce cell fate and differentiation in hematopoietic stem cells into fully differentiated hematopoietic cell types. The transcription factor zinc finger protein 148 (Zfp148) interacts with the hematopoietic transcription factor Gata1 and has been implicated to play an important role in primitive and definitive hematopoiesis in zebra fish and mouse chimeras. We have recently created a gene-trap knockout mouse model deficient for Zfp148, opening up for analyses of hematopoiesis in a conventional loss-of-function model in vivo. Here, we show that Zfp148-deficient neonatal and adult mice have normal or slightly increased levels of hemoglobin, hematocrit, platelets and white blood cells, compared to wild type controls. Hematopoietic lineages in bone marrow, thymus and spleen from Zfp148(gt/gt) mice were further investigated by flow cytometry. There were no differences in T-cells (CD4 and CD8 single positive cells, CD4 and CD8 double negative/positive cells) in either organ. However, the fraction of CD69- and B220-positive cells among lymphocytes in spleen was slightly lower at postnatal day 14 in Zfp148(gt/gt) mice compared to wild type mice. Our results demonstrate that Zfp148-deficient mice generate normal mature hematopoietic populations thus challenging earlier studies indicating that Zfp148 plays a critical role during hematopoietic development.
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| 27. |
- Nishio, Kumiko, et al.
(author)
-
Lysosomal processing of sulfatide analogs alters target NKT cell specificity and immune responses in cancer
- 2024
-
In: JOURNAL OF CLINICAL INVESTIGATION. - 0021-9738 .- 1558-8238. ; 134:4
-
Journal article (peer-reviewed)abstract
- In a structure-function study of sulfatides that typically stimulate type II NKT cells, we made an unexpected discovery. We compared analogs with sphingosine or phytosphingosine chains and 24-carbon acyl chains with 0-1-2 double bonds (C or pC24:0, 24:1, or 24:2). C24:1 and C24:2 sulfatide presented by the CD1d monomer on plastic stimulated type II, not type I, NKT cell hybridomas, as expected. Unexpectedly, when presented by bone marrow-derived DCs (BMDCs), C24:2 reversed specificity to stimulate type I, not type II, NKT cell hybridomas, mimicking the corresponding beta-galactosylceramide (beta GalCer) without sulfate. C24:2 induced IFN-gamma-dependent immunoprotection against CT26 colon cancer lung metastases, skewed the cytokine profile, and activated conventional DC subset 1 cells (cDC1s). This was abrogated by blocking lysosomal processing with bafilomycin A1, or by sulfite blocking of arylsulfatase or deletion of this enyzme that cleaves off sulfate. Thus, C24:2 was unexpectedly processed in BMDCs from a type II to a type I NKT cell-stimulating ligand, promoting tumor immunity. We believe this is the first discovery showing that antigen processing of glycosylceramides alters the specificity for the target cell, reversing the glycolipid's function from stimulating type II NKT cells to stimulating type I NKT cells, thereby introducing protective functional activity in cancer. We also believe our study uncovers a new role for antigen processing that does not involve MHC loading but rather alteration of which type of cell is responding
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| 28. |
- Novakova, Lenka, 1984, et al.
(author)
-
Cerebrospinal fluid sulfatide isoforms lack diagnostic utility in separating progressive from relapsing-remitting multiple sclerosis.
- 2023
-
In: Multiple sclerosis and related disorders. - 2211-0356. ; 74
-
Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system. The glycosphingolipid sulfatide, a lipid particularly enriched in the myelin sheath, has been shown to be involved the maintenance of this specific membrane structure. Sulfatide in cerebrospinal fluid (CSF) may reflect demyelination, a dominating feature of MS. We investigated the diagnostic utility of CSF sulfatide isoform levels to separate different courses or phenotypes of MS disease.This was a mono-center, cross-sectional study of relapsing-remitting MS (RRMS) (n=45) and progressive MS (PMS) (n=42) patients (consisting of primary PMS (n=17) and secondary PMS (n=25)) and healthy controls (n=19). In total, 20 sulfatide isoforms were measured in CSF by liquid chromatography-mass spectrometry.CSF total sulfatide concentrations, as well as CSF sulfatide isoform distribution, did not differ across the study groups, and their levels were independent of disease course/phenotype, disease duration, time to conversion to secondary PMS, age, and disability in MS patients.CSF sulfatide isoforms lack diagnostic and prognostic utility as a biomarker for progressive MS.
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| 29. |
- Novakova, Lenka, 1984, et al.
(author)
-
Sulfatide isoform pattern in cerebrospinal fluid discriminates progressive MS from relapsing-remitting MS
- 2018
-
In: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; 146:3, s. 322-332
-
Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Several biomarkers including proteins and lipids have been reported in MS cerebrospinal fluid (CSF), reflecting different aspects of the pathophysiology particularly of relapsing-remitting MS (RRMS). Sulfatide, abundant in the myelin sheath and a proposed target for autoimmune attack in MS, has been reported altered in MS CSF. Here, we investigated the potential of CSF sulfatide and its isoforms as biomarkers in MS. A highly sensitive and quantitative mass spectrometry method was employed to determine levels of sulfatide isoforms in CSF from RRMS and progressive MS (PMS) patients, and healthy donors (HD). We demonstrate that levels of total CSF sulfatide and C24:1, C26:1, and C26:1-OH isoforms were significantly increased in PMS compared with RRMS patients and HD, while C23:0-OH was significantly decreased in CSF from PMS patients compared to the other two groups. Multivariate discriminant analysis showed that CSF sulfatide isoform pattern in PMS patients was distinct and non-overlapping with that of RRMS patients and HD. Sulfatide levels did not correlate with tested biomarkers or clinical parameters. The results suggest that CSF sulfatide isoform levels may be used to discriminate the phenotype ofMS and might play a role in the progression of the disease.
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| 30. |
- Patel, Onisha, et al.
(author)
-
Recognition of CD1d-sulfatide mediated by a type II natural killer T cell antigen receptor.
- 2012
-
In: Nature immunology. - : Springer Science and Business Media LLC. - 1529-2916 .- 1529-2908. ; 13:9, s. 857-63
-
Journal article (peer-reviewed)abstract
- Natural killer T cells (NKT cells) are divided into type I and type II subsets on the basis of differences in their T cell antigen receptor (TCR) repertoire and CD1d-antigen specificity. Although the mode by which type I NKT cell TCRs recognize CD1d-antigen has been established, how type II NKT cell TCRs engage CD1d-antigen is unknown. Here we provide a basis for how a type II NKT cell TCR, XV19, recognized CD1d-sulfatide. The XV19 TCR bound orthogonally above the A' pocket of CD1d, in contrast to the parallel docking of type I NKT cell TCRs over the F' pocket of CD1d. At the XV19 TCR-CD1d-sulfatide interface, the TCRα and TCRβ chains sat centrally on CD1d, where the malleable CDR3 loops dominated interactions with CD1d-sulfatide. Accordingly, we highlight the diverse mechanisms by which NKT cell TCRs can bind CD1d and account for the distinct antigen specificity of type II NKT cells.
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| 31. |
- Pyz, Elwira, et al.
(author)
-
The complementarity determining region 2 of BV8S2 (V beta 8.2) contributes to antigen recognition by rat invariant NKT cell TCR.
- 2006
-
In: Journal of immunology (Baltimore, Md. : 1950). - 0022-1767. ; 176:12, s. 7447-7455
-
Journal article (peer-reviewed)abstract
- Invariant NKT cells (iNKT cells) are characterized by a semi-invariant TCR comprising an invariant alpha-chain paired with beta-chains with limited BV gene usage which are specific for complexes of CD1d and glycolipid Ags like alpha-galactosylceramide (alpha-GalCer). iNKT cells can be visualized with alpha-GalCer-loaded CD1d tetramers, and the binding of mouse CD1d tetramers to mouse as well as to human iNKT cells suggests a high degree of conservation in recognition of glycolipid Ags between species. Surprisingly, mouse CD1d tetramers failed to stain a discrete cell population among F344/Crl rat liver lymphocytes, although comprised iNKT cells are indicated by IL-4 and IFN-gamma secretion after alpha-GalCer stimulation. The arising hypothesis that rat iNKT TCR recognizes alpha-GalCer only if presented by syngeneic CD1d was then tested with the help of newly generated rat and mouse iNKT TCR-transduced cell lines. Cells expressing mouse iNKT TCR reacted to alpha-GalCer presented by rat or mouse CD1d and efficiently bound alpha-GalCer-loaded mouse CD1d tetramers. In contrast, cells expressing rat iNKT TCR responded only to alpha-GalCer presented by syngeneic CD1d and bound mouse CD1d tetramers only poorly or not at all. Finally, CD1d-dependent alpha-GalCer reactivity and binding of mouse CD1d tetramers was tested for cells expressing iNKT TCR comprising either rat or mouse AV14 (Valpha14) alpha-chains and wild-type or mutated BV8S2 (Vbeta8.2) beta-chains. The results confirmed the need of syngeneic CD1d as restriction element for rat iNKT TCR and identified the CDR2 of BV8S2 as an essential site for ligand recognition by iNKT TCR.
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| 32. |
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| 33. |
- Rhost, Sara, et al.
(author)
-
Administration of sulfatide to ameliorate type I diabetes in non-obese diabetic mice.
- 2014
-
In: Scandinavian journal of immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 79:4, s. 260-6
-
Journal article (peer-reviewed)abstract
- The endogenous glycosphingolipid sulfatide is a ligand for CD1d-restricted type II natural killer T (NKT) lymphocytes. Through the action of these cells,sulfatide treatment has been shown to modulate the immune response in mouse models for autoimmune diseases, infections and tumour immunity. Sulfatide exists naturally in different organs including the pancreas, where sulfatide colocalizes with insulin within the Langerhans islet b-cells, targets for the immune destruction in type 1 diabetes (T1D). Human T1D patients, but not patients with type 2 diabetes nor healthy individuals, have autoantibodies against sulfatide in serum, suggesting that sulfatide induces an immune response in the natural course of T1D in humans. Here, we investigate sulfatide as an autoantigen and a modulator of autoimmune disease in the murine model forT1D, the non-obese diabetic (NOD) mice. We demonstrate that aged NOD mice displayed serum autoantibody reactivity to sulfatide; however, this reactivity did not correlate with onset of T1D. Repeated administration of sulfatide did not result in an increase in serum reactivity to sulfatide. Moreover, a multidose sulfatide treatment of female NOD mice initiated at an early (5 weeks of age),intermediate (8 weeks of age) or late (12 weeks of age) phase of T1D progression did not influence the incidence of disease. Thus, we demonstrate that a fraction of NOD mice develop autoantibody reactivity to sulfatide; however, we fail to demonstrate that sulfatide treatment reduces the incidence of T1D in this mouse strain.
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| 34. |
|
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| 35. |
- Rhost, Sara, et al.
(author)
-
Identification of novel glycolipid ligands activating a sulfatide-reactive, CD1d-restricted, type II natural killer T lymphocyte
- 2012
-
In: European Journal of Immunology. - : Wiley. - 0014-2980. ; 42:11, s. 2851-2860
-
Journal article (peer-reviewed)abstract
- Sulfatide-reactive CD1d-restricted natural killer T (NKT) lymphocytes belong to the type II NKT cell subset with diverse TCRs, and have been found to regulate experimental auto-immune encephalomyelitis, tumor immunity, and experimental hepatitis in murine models. NKT cells can be activated by self-lipids presented by CD1d, manifested as autoreactivity. The identity of most of these self-lipids remains unknown. By isolating lipids from a CD1d-expressing, highly stimulatory antigen presenting cell, we identified isoforms of beta-glucosylceramide (GlcCer), with sphingosine and fatty acid chain lengths of C24:0 and C16:0, that activated a sulfatide-reactive type II NKT cell hybridoma. A screen of structurally related glycosphingolipids demonstrated beta-galactosylceramide (GalCer) as another ligand, and further, that the lysoforms were the most potent isoform of the glycosphingo-lipid ligands, followed by isoforms with a long fatty acid chain of C24. Thus, the same type II NKT cell was activated by several ligands, namely sulfatide, GlcCer, and GalCer. However, CD1d-dependent reactivity to antigen presenting cells lacking all GlcCer-based glycosphingolipids, or all glycosphingolipids, was maintained. This suggests that other endogenous, nonglycosphingolipid, lipid ligands contribute to steady-state autoreactivity by type II NKT cells.
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| 36. |
- Rhost, Sara, et al.
(author)
-
Identification of novel self lipids, GlcCer and GalCer, as CD1d-restricted ligands for type II NKT cells
- 2011
-
In: 6th International Symposium on CD1 and NKT Cells, September 23 - 27, 2011 - Chicago, Illinois. USA.
-
Conference paper (other academic/artistic)abstract
- NKT cells make up a potent immunomodulating subset of T lymphocytes that recognizes self-lipids presented by CD1d molecules. So far, the identity of most self-lipids presented by CD1d underlying the autoreactivity of NKT cells are unknown. In this study, we set out to identify self-lipids causing autoreactivity of a sulfatide reactive, CD1d restricted, murine type II NKT cell hybridoma (XV19). To this end we fractionated lipids from a highly stimulatory antigen presenting cell, A20CD1d TD, and found an active lipid fraction containing two isoforms of glucosylceramide (GlcCer) (Glcβ1-1'Cer), C24:0 and C16:0. The use of semi-synthetic isoforms confirmed that GlcCer stimulated XV19 NKT cells, In addition we identified the activation of XV19 cells by galactosylceramide (GalCer) isoforms (Galβ1-1'Cer), the precursors of sulfatide. The most potent isoform of the three glycosphingolipids was the lysoforms lacking the fatty acid chain followed by isoforms with the long fatty acid chain of C24. Thus, one NKT cell hybridoma could recognize sulfatide > GlcCer > GalCer in a CD1d-dependent manner. Ongoing studies are investigating the role of the identified ligands for the CD1d-dependent autoreacticity of the XV19 NKT hybridoma cells.
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| 37. |
- Rhost, Sara, et al.
(author)
-
Immunomodulatory Type II Natural Killer T Lymphocytes in Health and Disease
- 2012
-
In: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 76:3, s. 246-255
-
Journal article (peer-reviewed)abstract
- Natural killer T (NKT) lymphocytes are a beta T cells activated by lipid-based ligands presented on the non-polymorphic CD1d-molecule. Type I NKT cells that carry an invariant Va14 (in the mouse) or Va24 (in humans) T cell receptor a-chain rearrangement have received significant attention for their involvement in a diversity of immune reactions. Their sister population, CD1d-restricted type II NKT cells, has been more difficult to study because of the lack of molecular markers that specify these cells. In the last few years, however, significant progress has been made, demonstrating that type II NKT cells have unique functions in immune responses to tumours and infections, in autoimmunity, obesity and graft-versus-host disease. Type II NKT cells appear more frequent than type I NKT cells in humans and accumulate in certain diseases such as ulcerative colitis, hepatitis and multiple myeloma. Recently, novel type II NKT cell ligands have been identified, and it is becoming clear that the type II NKT cell population may be oligoclonal. Here, we review the recent progress in the study of type II NKT cells, supporting the view that type II NKT cells may be attractive targets for immunotherapy.
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| 38. |
- Rolf, Julia, 1979, et al.
(author)
-
Molecular profiling reveals distinct functional attributes of CD1d-restricted natural killer (NK) T cell subsets.
- 2008
-
In: Molecular immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 45:9, s. 2607-20
-
Journal article (peer-reviewed)abstract
- CD1d-restricted natural killer T (NKT) cells can have multiple effects on an immune response, including the activation, regulation and attraction of innate immune cells, and modulation of adaptive immunity. Recent studies reveal that there are distinct subsets of NKT cells which selectively perform some of the functions attributed to CD1d-restricted cells, but the mechanisms underlying these functional differences have not been resolved. Our aim in this study was to identify novel NKT cell associated traits that would provide important insight into NKT cell activation and function. To this end, we have performed gene expression profiling of two separate subsets of NKT cells, analyzing genes differentially expressed in these cells compared to conventional CD4(+)NK1.1(-) T cells. We identify different sets of genes over expressed in each of the two NKT cell types, as well as genes that are common to the two CD1d-restricted NKT cell populations analyzed. A large number of these genes are highly relevant for NKT cell development, activation and function. Each NKT subtype displayed a unique set of chemokine receptors, integrins and molecules related to effector function, supporting the notion that distinct NKT cells can be selectively engaged and have diverse functions in different types of immune reactions.
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| 39. |
- Sedimbi, Sai Kiran, 1982, et al.
(author)
-
PAMP mediated activation of type II NKT cells
- 2011
-
In: 6th International Symposium on CD1d and NK T cells, September 23-27, 2011, Chicago, IL, USA.
-
Conference paper (other academic/artistic)abstract
- Type 2 NK T cells are known to have immuno-stimulatory/regulatory effects on innate and adaptive immune responses to infections, tumors and autoimmunity. However, there is a paucity of information regarding the mechanism of activation of type 2 NK T cells in various immune responses. We aim to identify the signals required for activation of type 2 NK T cells by pathogen associated molecular patterns (PAMPs). Using type 2 NK T cells from a transgenic mouse model (24αβ B6: over expressing Vα3.2/Vβ9 type 2 NK T cells), we performed co-culture experiments with enriched primary type 2 NK T cells and bone marrow derived dendritic cells (DC) from mice that were WT or harbouring various gene deletions. Several TLR ligands activated the type 2 NK T cells in the co-cultures. The experiments revealed that type 2 NK T cells were not activated directly by PAMPs, but required the presence of antigen presenting cells such as DC. Transwell experiments suggest that activation occurred in a cell-contact dependent fashion. Further, we find that IL12 was absolutely essential for activation, while type I interferons appear to be dispensible. Surprisingly, CD1d was not required for type 2 NK T cell activation by PAMPs. Our results suggest that in addition to IL-12, other DC mediated signals were required for the CD1d-independent activation of type 2 NK T cells by PAMPs. Ongoing studies are investigating further which signals are required for NKT cell activation and the type of immune response induced.
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| 40. |
- Singh, Avadhesh Kumar, 1982, et al.
(author)
-
Defining a novel subset of CD1d-dependent type II natural killer T cells using natural killer cell-associated markers
- 2019
-
In: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 90:3
-
Journal article (peer-reviewed)abstract
- Natural killer T (NKT) cells are alpha beta T cell receptor (TCR) expressing innate-like T cells that display natural killer (NK) cell markers. Based on TCR characteristics, they are divided into two groups restricted to the MHC class I-like molecule CD1d. Type I NKT cells, most extensively studied, are identified by a semi-invariant V alpha 14-J alpha 18 (mouse, V alpha 24-J alpha 18 in humans) TCR reactive to the prototypic ligand alpha-galactosylceramide presented on CD1d. In contrast, type II NKT cells display diverse TCR reacting to different CD1d-presented ligands. There are no reagents that identify all type II NKT cells, limiting their exploration. Here, we searched for novel type II NKT cells by comparing J alpha 18(-/-)MHCII(-/-) mice that harbour type II but not type I NKT cells, and CD1d(-/-)MHCII(-/-) mice, lacking all NKT cells. We identified significantly larger populations of CD4(+) and CD4(-)CD8(-) (double negative, DN) TCR beta(+) cells expressing NKG2D or NKG2A/C/E in J alpha 18(-/-)MHCII(-/-) mice compared with CD1d(-/-)MHCII(-/-) mice, suggesting that 30%-50% of these cells were type II NKT cells. They expressed CD122, NK1.1, CXCR3 and intermediate/low levels of CD45RB. Further, the CD4(+) subset was CD69(+), while the DN cells were CD49b(+) and CD62L(+). Both subsets expressed the NKT cell-associated promyelocytic leukaemia zinc finger (PLZF) transcription factor and Tbet, while fewer cells expressed ROR gamma t. NKG2D(+) CD4(+) and DN populations were producers of IFN-gamma, but rarely IL-4 and IL-17. Taken together, we identify a novel subset of primary CD4(+) and DN type II NKT cells that expresses NKG2 receptors have typical NKT cell phenotypes and a TH1-like cytokine production.
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| 41. |
- Singh, Avadhesh Kumar, 1982, et al.
(author)
-
High Interferon-γ Uniquely in Vδ1 T Cells Correlates with Markers of Inflammation and Axonal Damage in Early Multiple Sclerosis.
- 2017
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
-
Journal article (peer-reviewed)abstract
- We have identified a population of T lymphocytes in peripheral blood, Vδ1 TCRγδ T lymphocytes, which unexpectedly was uniquely expressing high production of interferon-γ in newly diagnosed, untreated multiple sclerosis (MS) patients. IFN-γ production in this population distinctly correlated to parameters of clinical disease activity, inflammation, and neuronal damage. These Vδ1 T lymphocytes belong to a population of innate T lymphocytes that recognize antigen in the context of CD1d/CD1c and which include reactivity to the myelin glycosphingolipid sulfatide. Importantly, patients treated with natalizumab, blocking leukocyte transmigration to central nervous system, had completely normalized levels of interferon-γ-producing Vδ1 T lymphocytes. A biomarker and early sign of demyelinating disease in MS is much warranted and would help identify immunopathogenesis and prognosis of disease as well as monitor success with adequate treatment. The present study identifies the Vδ1 T lymphocytes as an early marker of MS and a possible link to understanding the disease etiology.
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| 42. |
- Singh, Avadhesh Kumar, 1982, et al.
(author)
-
Type II NKT Cells: An Elusive Population With Immunoregulatory Properties
- 2018
-
In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
-
Journal article (peer-reviewed)abstract
- Natural killer T (NKT) cells are unique unconventional T cells that are reactive to lipid antigens presented on the non-polymorphic major histocompatibility class (MHC) I-like molecule CD1d. They have characteristics of both innate and adaptive immune cells, and have potent immunoregulatory roles in tumor immunity, autoimmunity, and infectious diseases. Based on their T cell receptor (TCR) expression, NKT cells are divided into two subsets, type I NKT cells with an invariant TCR alpha-chain (V alpha 24 in humans, V alpha 14 in mice) and type II NKT cells with diverse TCRs. While type I NKT cells are well-studied, knowledge about type II NKT cells is still limited, and it is to date only possible to identify subsets of this population. However, recent advances have shown that both type I and type II NKT cells play important roles in many inflammatory situations, and can sometimes regulate the functions of each other. Type II NKT cells can be both protective and pathogenic. Here, we review current knowledge on type II NKT cells and their functions in different disease settings and how these cells can influence immunological outcomes.
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| 43. |
- Song, J., et al.
(author)
-
Extracellular matrix of secondary lymphoid organs impacts on B-cell fate and survival
- 2013
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 110:31
-
Journal article (peer-reviewed)abstract
- We describe a unique extracellular matrix (ECM) niche in the spleen, the marginal zone (MZ), characterized by the basement membrane glycoproteins, laminin alpha 5 and agrin, that promotes formation of a specialized population of MZ B lymphocytes that respond rapidly to blood-borne antigens. Mice with reduced laminin alpha 5 expression show reduced MZ B cells and increased numbers of newly formed (NF) transitional B cells that migrate from the bone marrow, without changes in other immune or stromal cell compartments. Transient integrin alpha 6 beta 1-mediated interaction of NF B cells with laminin alpha 5 in the MZ supports the MZ B-cell population, their long-term survival, and antibody response. Data suggest that the unique 3D structure and biochemical composition of the ECM of lymphoid organs impacts on immune cell fate.
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| 44. |
- Song, J., et al.
(author)
-
The extracellular matrix of lymph node reticular fibers modulates follicle border interactions and germinal center formation
- 2023
-
In: iScience. - 2589-0042. ; 26:5
-
Journal article (peer-reviewed)abstract
- Germinal center (GC) formation and antibody production in lymph node follicles require coordinated interactions between B-cells, T-cells and dendritic cells (DCs), orchestrated by the extracellular matrix-rich reticular fiber (RF) network. We describe a unique laminin 523-containing RF network around and between follicles that associates with PDGFrecb(high) CCL19(low)gp38(low) fibroblastic reticular cells (FRC). In the absence of FRC expression of laminin alpha 5 (pdgfrb-cre:Lama5(fl/fl)), pre-Tfh-cells, B-cells and DCs are displaced from follicle borders, correlating with fewer Tfh-cells and GC B-cells. Total DCs are not altered in pdgfrb-cre: Lama5(fl/fl) mice, but cDC2s, which localize to laminin alpha 5 in RFs at follicle borders, are reduced. In addition, PDGFrecb(high)CCL19(low)gp38(low) FRCs show lower Ch25h expression, required for 7 alpha,25-dihydroxycholesterol synthesis that attracts pre-Tfh-cells, B-cells and DCs to follicle borders. We propose that RF basement membrane components represent a type of tissue memory that guides the localization and differentiation of both specialized FRC and DC populations, required for normal lymph node function.
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| 45. |
- Ström, Åsa, et al.
(author)
-
Involvement of the CD1d-Natural killer T cell pathway in neointima formation after vascular injury
- 2007
-
In: CIRCULATION RESEARCH. - 0009-7330. ; 101:8
-
Journal article (peer-reviewed)abstract
- Recent studies have established that the immune system plays an important role in the development of atherosclerosis. However, its role in regulating the arterial response to mechanical injury is less well studied. Arterial injury is associated with local accumulation of antibodies, and mice lacking functional T and B cells exhibit increased neointima formation, indicating that adaptive immune responses to neoantigens in the damaged tissue modulate the vascular repair process. To study the role of lipid antigen presentation in the arterial response to injury, we analyzed neointima formation in mice deficient in the lipid antigen-presenting molecule CD1d using a carotid collar model. As compared with control mice, neointima formation was reduced by >60% (P<0.01) in CD1d-/- mice. Moreover, carotid injury of wild-type C57BL/6 mice was associated with expansion of CD1d-restricted natural killer T cells in the spleen and accumulation of natural killer T cells in the periadventitial space of injured arteries. The results suggest that presentation of lipid antigens through the CD1d-natural killer T cell pathway modulates vascular repair responses.
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| 46. |
- Tatituri, R. V. V., et al.
(author)
-
Recognition of microbial and mammalian phospholipid antigens by NKT cells with diverse TCRs
- 2013
-
In: Proceedings of the National Academy of Science of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 110:5, s. 1827-1832
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Journal article (peer-reviewed)abstract
- CD1d-restricted natural killer T (NKT) cells include two major subgroups. The most widely studied are V alpha 14J alpha 18(+) invariant NKT (iNKT) cells that recognize the prototypical alpha-galactosylceramide antigen, whereas the other major group uses diverse T-cell receptor (TCR) alpha-and beta-chains, does not recognize alpha-galactosylceramide, and is referred to as diverse NKT (dNKT) cells. dNKT cells play important roles during infection and autoimmunity, but the antigens they recognize remain poorly understood. Here, we identified phosphatidylglycerol (PG), diphosphatidylglycerol (DPG, or cardiolipin), and phosphatidylinositol from Mycobacterium tuberculosis or Corynebacterium glutamicum as microbial antigens that stimulated various dNKT, but not iNKT, hybridomas. dNKT hybridomas showed distinct reactivities for diverse antigens. Stimulation of dNKT hybridomas by microbial PG was independent of Toll-like receptor-mediated signaling by antigen-presenting cells and required lipid uptake and/or processing. Furthermore, microbial PG bound to CD1d molecules and plate-bound PG/CD1d complexes stimulated dNKT hybridomas, indicating direct recognition by the dNKT cell TCR. Interestingly, despite structural differences in acyl chain composition between microbial and mammalian PG and DPG, lipids from both sources stimulated dNKT hybridomas, suggesting that presentation of microbial lipids and enhanced availability of stimulatory self-lipids may both contribute to dNKT cell activation during infection.
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| 47. |
- Tripathi, Prabhanshu, et al.
(author)
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Innate and adaptive stimulation of murine diverse NKT cells result in distinct cellular responses.
- 2019
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In: European journal of immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 49:3, s. 443-453
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Journal article (peer-reviewed)abstract
- Natural killer T (NKT) cells recognize glycolipids presented on CD1d. They share features of adaptive T lymphocytes and innate NK cells, and mediate immunoregulatory functions via rapid production of cytokines. Invariant (iNKT) and diverse (dNKT) NKT cell subsets are defined by their TCR. The immunological role of dNKT cells, that do not express the invariant TCRα-chain used by iNKT cells, is less well explored than that of iNKT cells. Here, we investigated signals driving Toll-like receptor (TLR) ligand activation of TCR-transgenic murine dNKT cells. IFN-γ production by dNKT cells required dendritic cells (DC), cell-to-cell contact and presence of TLR ligands. TLR-stimulated DC activated dNKT cells to secrete IFN-γ in a CD1d-, CD80/86- and type I IFN-independent manner. In contrast, a requirement for IL-12p40, and a TLR ligand-selective dependence on IL-18 or IL-15 was observed. TLR ligand/DC stimulation provoked early secretion of pro-inflammatory cytokines by both CD62L+ and CD62L- dNKT cells. However, proliferation was limited. In contrast, TCR/co-receptor-mediated activation resulted in proliferation and delayed production of a broader cytokine spectrum preferentially in CD62L- dNKT cells. Thus, innate (TLR ligand/DC) and adaptive (TCR/co-receptor) stimulation of dNKT cells resulted in distinct cellular responses that may contribute differently to the formation of immune memory.
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| 48. |
- Wang, Ying, et al.
(author)
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Natural Killer T-Cell Agonist α-Galactosylceramide and PD-1 Blockade Synergize to Reduce Tumor Development in a Preclinical Model of Colon Cancer
- 2020
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Journal article (peer-reviewed)abstract
- Murine and human invariant natural killer T (iNKT) lymphocytes are activated by α-galactosylceramide (α-GalCer) presented on CD1d. α-GalCer was first described as a lipid that had strong anti-metastatic effects in a mouse melanoma model, and it has subsequently been shown to induce efficient iNKT cell dependent tumor immunity in several tumor models. We have shown that α-GalCer treatment leads to a weak reduction of polyp burden in the autochthonous ApcMin/+ mouse model for human colon cancer, however this treatment resulted in upregulation of the inhibitory receptor PD-1 on iNKT cells. While anti-PD-1 treatment can prevent immune-suppression in other cancer types, human colon cancer is generally resistant to this treatment. Here we have used the ApcMin/+ model to investigate whether a combined treatment with α-GalCer and PD-1 blockade results in improved effects on polyp development. We find that PD-1 expression was high on T cells in polyps and lamina propria (LP) of ApcMin/+ mice compared to polyp free Apc+/+ littermates. Anti-PD-1 treatment alone promoted Tbet expression in iNKT cells and CD4 T cells, but did not significantly reduce polyp numbers. However, the combined treatment with anti-PD-1 and α-GalCer had synergistic effects, resulting in highly significant reduction of polyp numbers in the small and large intestine. Addition of PD-1 blockade to α-GalCer treatment prevented loss of iNKT cells that were skewed towards a TH1-like iNKT1 phenotype specifically in polyps. It also resulted in TH1 skewing and increased granzyme B expression of CD4 T cells. Taken together this demonstrates that a combination of immune stimulation targeting iNKT cells and checkpoint blockade may be a promising approach to develop for improved tumor immunotherapy. © Copyright © 2020 Wang, Bhave, Yagita and Cardell.
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| 49. |
- Wang, Ying, et al.
(author)
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Promotion or Suppression of Murine Intestinal Polyp Development by iNKT Cell Directed Immunotherapy
- 2019
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Journal article (peer-reviewed)abstract
- The glycosphingolipid alpha-galactosylceramide (alpha-GalCer) is a well- described immune activator with strong anti-tumor properties in animal models. It is presented on CD1d and acts by stimulating the invariant, type I, natural killer T (iNKT) lymphocytes to rapidly secrete TH1 and TH2 associated cytokines. This in turn promotes activation of a diversity of immune cells including natural killer (NK) cells with anti-tumor functions. Prior to tumor development, iNKT cells can also perform tumor surveillance and naturally protect from emergence of cancer. In contrast, we have recently demonstrated that iNKT cells naturally promote polyps in the spontaneous murine adenomatous polyposis coli (Apc) Apc(Min/+) model for colon cancer, associated with suppressed TH1 immunity and enhanced immunoregulation. Here we investigated whether iNKT cell directed immunotherapy could subvert the polyp promoting function of iNKT cells and reduce polyp growth in this model. We treated Apc(Min/+) mice with alpha-GalCer, or synthetic derivatives of this ligand (C-glycoside and C20:2) that have enhanced immunoregulatory properties. Treatment with iNKT cell ligands led to increased iNKT cell division, but reduced iNKT cell frequencies, lower NK1.1 expression and elevation of PD-1. Apc(Min/+) mice that had been treated either long-term (5-15 weeks of age), or short-term (12-15 weeks of age) with alpha-GalCer demonstrated a significant decrease in polyp burden. Surprisingly, long-term treatment with the TH1 biasing ligand C-glycoside did not have significant effects on polyps, while long-termtreatment with the TH2 biasing ligand C20: 2 enhanced polyp growth. In stark contrast, short-term treatment with C20: 2 led to reduction in polyp numbers and size. Reduced polyp burden after long-term treatment was associated with increased expression of genes indicating a pro-inflammatory polyp microenvironment. Polyp-reducing short-term treatment led to CD8 T cell activation specifically in polyps, and decreased tumor infiltrating and splenic macrophages, and a switch toward a pro-inflammatory phenotype. Thus, iNKT cell directed therapy could subvert the natural polyp enhancing function of iNKT cells, overcome immunosuppression, and reduce polyps. However, different iNKT cell activating ligands had opposite effects, and the timing of treatment had a major influence on outcomes.
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| 50. |
- Wang, Ying, et al.
(author)
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The Yin and Yang of invariant Natural Killer T Cells in Tumor immunity-Suppression of Tumor immunity in the intestine
- 2018
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
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Research review (peer-reviewed)abstract
- CD1d-restricted invariant natural killer T (iNKT) cells are known as early responding, potent regulatory cells of immune responses. Besides their established role in the regulation of inflammation and autoimmune disease, numerous studies have shown that iNKT cells have important functions in tumor immunosurveillance and control of tumor metastasis. Tumor-infiltrating T helper 1 (TH1)/cytotoxic T lymphocytes have been associated with a positive prognosis. However, inflammation has a dual role in cancer and chronic inflammation is believed to be a driving force in many cancers as exemplified in patients with inflammatory bowel disease that have an increased risk of colorectal cancer. Indeed, NKT cells promote intestinal inflammation in human ulcerative colitis, and the associated animal model, indicating that NKT cells may favor tumor development in intestinal tissue. In contrast to other cancers, recent data from animal models suggest that iNKT cells promote tumor formation in the intestine by supporting an immunoregulatory tumor microenvironment and suppressing TH1 antitumor immunity. Here, we review the role of iNKT cells in suppression of tumor immunity in light of iNKT-cell regulation of intestinal inflammation. We also discuss suppression of immunity in other situations as well as factors that may influence whether iNKT cells have a protective or an immunosuppressive and tumor-promoting role in tumor immunity.
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