| 1. |
- Cucak, Helena, et al.
(författare)
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Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells.
- 2009
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Ingår i: Immunity. - : Elsevier BV. - 1097-4180 .- 1074-7613. ; 31:3, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- T follicular helper (Tfh) cells represent a recently defined CD4(+) T cell subset characterized by the expression of the chemokine receptor CXCR5 and an enhanced ability to support B cells to mount antibody responses. Here, we demonstrate that lymph-node-resident CXCR5(+) Tfh cells and gut-homing integrin alpha(4)beta(7)-expressing T helper cells are generated as separate subsets in the gut-draining mesenteric lymph nodes. Type I interferon signaling in dendritic cells and in nonhematopoietic cells selectively stimulates Tfh cell development in response to antigen in conjunction with Toll-like receptor (TLR)3 or TLR4 agonists. Consistent with this, the ability of dendritic cells to produce the cytokine IL-6, required for in vivo Tfh differentiation, and antibody affinity maturation are both reduced in absence of type I interferon signaling. Thus, our results identify type I interferon as a natural adjuvant that selectively supports the generation of lymph node resident Tfh cells.
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| 2. |
- Alsén, Samuel, et al.
(författare)
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Antigen-Presenting B Cells Program the Efferent Lymph T Helper Cell Response
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- B cells interact with T follicular helper (Tfh) cells in germinal centers (GCs) to generate high-affinity antibodies. Much less is known about how cognate T-B-cell interactions influence Th cells that enter circulation and peripheral tissues. Therefore, we generated mice lacking MHC-II expressing B cells and, by thoracic duct cannulation, analyzed Th cells in the efferent lymph at defined intervals post-immunization. Focusing on gut-draining mesenteric lymph nodes (MLNs), we show that antigen-specific alpha(4)beta(+)(7) gut-homing effector Th cells enter the circulation prior to CXCR5(+)PD-1(+) Tfh-like cells. B cells appear to have no or limited impact on the early generation and egress of gut-homing Th cells but are critical for the subsequent appearance of Tfh-like cells that peak in the lymph before GCs have developed. At this stage, antigen-presenting B cells also reduce the proportion of alpha(4)beta(+)(7) Th cells in the MLN and efferent lymph. Furthermore, cognate B-cell interaction drives a broad transcriptional program in Th cells, including IL-4 that is confined to the Tfh cell lineage. The IL-4-producing Tfh-like cells originate from Bcl6(+) precursors in the LNs and have gut-homing capacity. Hence, B cells program the efferent lymph Th cell response within a limited window of time after antigenic challenge.
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| 3. |
- Dahlgren, Madelene, et al.
(författare)
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T Follicular Helper, but Not Th1, Cell Differentiation in the Absence of Conventional Dendritic Cells
- 2015
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 194:11, s. 5187-5199
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Tidskriftsartikel (refereegranskat)abstract
- Development of long-lived humoral immunity is dependent on CXCR5-expressing T follicular helper (Tfh) cells, which develop concomitantly to effector Th cells that support cellular immunity. Conventional dendritic cells (cDCs) are critical APCs for initial priming of naive CD4(+) T cells but, importantly, also provide accessory signals that govern effector Th cell commitment. To define the accessory role of cDCs during the concurrent development of Tfh and effector Th1 cells, we performed high-dose Ag immunization in conjunction with the Th1-biased adjuvant polyinosinic: polycytidylic acid (pI:C). In the absence of cDCs, pI: C failed to induce Th1 cell commitment and IgG2c production. However, cDC depletion did not impair Tfh cell differentiation or germinal center formation, and long-lived IgG1 responses of unaltered affinity developed in mice lacking cDCs at the time point for immunization. Thus, cDCs are required for the pI: C-driven Th1 cell fate commitment but have no crucial accessory function in relation to Tfh cell differentiation.
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| 4. |
- Hägerbrand, Karin, et al.
(författare)
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MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103(+) Dendritic Cells Independently of TNF-alpha and the Gut Microbiota
- 2015
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 195:6, s. 2888-2899
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Tidskriftsartikel (refereegranskat)abstract
- Intestinal homeostasis and induction of systemic tolerance to fed Ags (i.e., oral tolerance) rely on the steady-state migration of small intestinal lamina propria dendritic cells (DCs) into draining mesenteric lymph nodes (MLN). The majority of these migratory DCs express the a integrin chain CD103, and in this study we demonstrate that the steady-state mobilization of CD103(+) DCs into the MLN is in part governed by the IL-1R family/TLR signaling adaptor molecule MyD88. Similar to mice with complete MyD88 deficiency, specific deletion of MyD88 in DCs resulted in a 50-60% reduction in short-term accumulation of both CD103(+)CD11b(+) and CD103(+)CD11b(-) DCs in the MLN. DC migration was independent of caspase-1, which is responsible for the inflammasome-dependent proteolytic activation of IL-1 cytokine family members, and was not affected by treatment with broad-spectrum antibiotics. Consistent with the latter finding, the proportion and phenotypic composition of DCs were similar in mesenteric lymph from germ-free and conventionally housed mice. Although TNF-alpha was required for CD103(+) DC migration to the MLN after oral administration of the TLR7 agonist R848, it was not required for the steady-state migration of these cells. Similarly, TLR signaling through the adaptor molecule Toll/IL-1R domain-containing adapter inducing IFN-beta and downstream production of type I IFN were not required for steady-state CD103(+) DC migration. Taken together, our results demonstrate that MyD88 signaling in DCs, independently of the microbiota and TNF-alpha, is required for optimal steady-state migration of small intestinal lamina propria CD103(+) DCs into the MLN.
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| 5. |
- Stenstad, Hanna, et al.
(författare)
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Gut-associated lymphoid tissue-primed CD4+ T cells display CCR9-dependent and -independent homing to the small intestine.
- 2006
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 107:9, s. 3447-54
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Tidskriftsartikel (refereegranskat)abstract
- CD4(+) T-cell entry to the intestinal mucosa is central to the generation of mucosal immunity as well as chronic intestinal inflammation, yet the mechanisms regulating this process remain poorly defined. Here we show that murine small intestinal CD4(+) lamina propria lymphocytes express a heterogeneous but restricted array of chemokine receptors including CCR5, CCR6, CCR9, CXCR3, and CXCR6. CD4(+) T-cell receptor transgenic OT-II cells activated in mesenteric lymph nodes acquired a distinct chemokine receptor profile, including expression of CCR6, CCR9, and CXCR3 that was only partially reproduced in vitro after priming with mesenteric lymph node dendritic cells. A subset of these effector CD4(+) T cells, expressing CD69 and alpha(4)beta(7), entered the intestinal lamina propria and the majority of these cells expressed CCR9. CCR9(-/-) OT-II cells were disadvantaged in their ability to localize to the intestinal lamina propria; however, they were readily detected at this site and expressed alpha(4)beta(7), but little CCR2, CCR5, CCR6, CCR8, CCR10, CXCR3, or CXCR6. Thus, whereas CD4(+) T cells activated in gut-associated lymphoid tissue express a restricted chemokine receptor profile, including CCR9, targeting both CCR9-dependent and CCR9-independent entry mechanisms is likely to be important to maximally inhibit accumulation of these cells within the small intestinal mucosa.
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| 6. |
- Movert, Elin, et al.
(författare)
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Streptococcal M protein promotes IL-10 production by cGAS-independent activation of the STING signaling pathway
- 2018
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7374 .- 1553-7366. ; 14:3
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Tidskriftsartikel (refereegranskat)abstract
- From an evolutionary point of view a pathogen might benefit from regulating the inflammatory response, both in order to facilitate establishment of colonization and to avoid life-threatening host manifestations, such as septic shock. In agreement with this notion Streptococcus pyogenes exploits type I IFN-signaling to limit detrimental inflammation in infected mice, but the host-pathogen interactions and mechanisms responsible for induction of the type I IFN response have remained unknown. Here we used a macrophage infection model and report that S. pyogenes induces anti-inflammatory IL-10 in an M protein-dependent manner, a function that was mapped to the B- and C-repeat regions of the M5 protein. Intriguingly, IL-10 was produced downstream of type I IFN-signaling, and production of type I IFN occurred via M protein-dependent activation of the STING signaling pathway. Activation of STING was independent of the cytosolic double stranded DNA sensor cGAS, and infection did not induce detectable release into the cytosol of either mitochondrial, nuclear or bacterial DNA–indicating DNA-independent activation of the STING pathway in S. pyogenes infected macrophages. These findings provide mechanistic insight concerning how S. pyogenes induces the type I IFN response and identify a previously unrecognized macrophage-modulating role for the streptococcal M protein that may contribute to curb the inflammatory response to infection.
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| 7. |
- Gustafsson, Tobias, et al.
(författare)
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Direct interaction between cholera toxin and dendritic cells is required for oral adjuvant activity
- 2013
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 43:7, s. 1779-1788
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Tidskriftsartikel (refereegranskat)abstract
- Cholera toxin (CT) binds to GM1-ganglioside receptors present on all nucleated cells. Despite this, it is a very potent mucosal adjuvant that has a dramatic impact on immune cells, as well as nerve and epithelial cells, causing diarrhea. This fact has hampered our understanding of whether the adjuvanticity of CT is direct or indirect, as cells that bind CT may or may not be involved in its adjuvant function. The mucosal barrier is maintained by tight junctions between epithelial cells but dendritic cells (DCs) can protrude luminal dendrites. Here we investigated which cells are involved in the immune augmenting effect of CT. We explored oral immunizations with ovalbumin (OVA) and CT in bone marrow chimeric mice deficient in GM1-ganglioside in defined cellular subsets. We found that chimeric mice lacking GM1 in nonhematopoietic cells, including epithelial cells, mounted an unaltered intestinal IgA response. In contrast, chimeric mice lacking GM1-expressing hematopoietic cells in general, or specifically GM1-expressing conventional DCs (cDCs), largely failed to elicit anti-OVA adaptive immune responses. Therefore, the adjuvanticity of CT does not require epithelial activation, but is directly dependent on the binding of CT to gut cDCs via GM1-ganglioside. These results could have important implications for the generation of novel oral adjuvants.
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| 8. |
- Johansson Lindbom, Bengt
(författare)
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Regulatory properties of dendritic cells and B cells in adaptive immunity
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is based upon four original papers in which human dendritic cells (DCs) and B cells have been analyzed in terms of how they influence the character of adaptive immune responses. DCs isolated from human tonsils were found to possess a capacity to directly regulate proliferation, isotype switching, and antibody production in B cells. DC-produced cytokines, including IL-13, were identified as critical mediators of these B cell responses. Furthermore, gene chip technology was used to evaluate the nature and kinetics of the global gene expression taking place in monocyte-derived DCs exposed to inflammatory agents. Obtained results revealed an extensive and temporal reprogramming of these cells in response to TNF-a, IL-1b, plus mediators released by activated monocytes. The altered gene expression was represented by a pronounced upregulation of a number of mRNAs encoding proteins with established functions in the regulation of both T and B cell responses. This transcriptional reorganization may reflect the effect of in vivo released inflammatory mediators, indicating that DCs can be fully matured to activate adaptive immunity in response to tissue inflammation. Furthermore, also the role of B cells in immune regulation was investigated. Antigen-activated B cells within germinal centers (GC) were found to produce the Th2-polarizing cytokine IL-4 and consequently they could elicit Th2-differentiation in vitro. In agreement with this in vitro observation, a Th2 precursor subset was identified in human tonsil and demonstrated to uniformly display a GC-associated CXCR5high phenotype. Therefore Th2-development in human tonsils appears to selectively occur within GCs and to be supported by B cells secreting IL-4. Moreover, IL-4-producing B cells were also identified within follicles located in colon mucosa, indicating that B cell-dependent Th2 development can take place in several of the mucosa associated lymphoid tissues. Finally, functional properties of the previously described CD57+ GC Th cells were addressed and obtained results showed that these cells represent anergized T cells. These data thus suggest that B cells and GCs regulate CD4+ T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells or by furnishing T cell-unresponsiveness. In conclusion, I propose that Th cell polarization may be subjected to a counterbalanced regulation, where DC-produced IL-12 and/or IFN-a/b promote Th1-differentiation, whereas GCs and B cells preferentially furnish Th2-development but also contribute to suppression of T cell responses.
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| 9. |
- Schiött, Åsa, et al.
(författare)
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CD27- CD4+ memory T cells define a differentiated memory population at both the functional and transcriptional levels
- 2004
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 113:3, s. 363-370
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Tidskriftsartikel (refereegranskat)abstract
- The memory T-cell population is a heterogeneous population, including both effector cells, which exert a direct secondary immune response, and resting or intermediate cells, which serve as a reservoir and exert a possible regulatory role. To further dissect the T-cell memory population residing in the CD4 +CD45RO+ T-cell pool, we studied the functional properties of memory populations identified by the CD27 marker. This marker clearly divides the memory population into two groups. One group consists of effector cells lacking CD27 and displaying a high antigen recall response. The other group consists of an intermediate memory population, displaying CD27. This latter group lacks an antigen recall response and requires costimulation for T-cell receptor triggering. To evaluate the function of the CD27+ memory pool, we analysed the transcriptional profile, using high-density microarray technology. These gene data strongly support the different functional profiles of CD27+ and CD27+ memory populations, in terms of protein expression and the capacity to respond to antigen.
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| 10. |
- Alyamani, Manar, et al.
(författare)
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Alkaline sphingomyelinase (NPP7) impacts the homeostasis of intestinal T lymphocyte populations
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background and aim: Alkaline sphingomyelinase (NPP7) is expressed by intestinal epithelial cells and is crucial for the digestion of dietary sphingomyelin. NPP7 also inactivates proinflammatory mediators including platelet-activating factor and lysophosphatidylcholine. The aim of this study was to examine a potential role for NPP7 in the homeostasis of the intestinal immune system. Methods: We quantified the numbers of B-lymphocytes, plasma cells, T-lymphocytes including regulatory T-lymphocytes (Tregs), natural killer cells, dendritic cells, macrophages, and neutrophils, in the small and large intestines, the mesenteric lymph nodes and the spleens of heterozygous and homozygous NPP7 knockout (KO) and wildtype (WT) mice. Tissues were examined by immunohistochemistry and stainings quantified using computerized image analysis. Results: The numbers of both small and large intestinal CD3ε+, CD4+, and CD8α+ T-lymphocytes were significantly higher in NPP7 KO compared to WT mice (with a dose-response relationship in the large intestine), whereas Treg numbers were unchanged, and dendritic cell numbers reduced. In contrast, the numbers of CD3ε+ and CD4+ T-lymphocytes in mesenteric lymph nodes were significantly reduced in NPP7 KO mice, while no differences were observed in spleens. The numbers of B-lymphocytes, plasma cells, natural killer cells, macrophages, and neutrophils were similar between genotypes. Conclusion: NPP7 contributes to the regulation of dendritic cell and T-lymphocyte numbers in mesenteric lymph nodes and both the small and large intestines, thus playing a role in the homeostasis of gut immunity. Although it is likely that the downstream effects of NPP7 activity involve the sphingomyelin metabolites ceramide and spingosine-1-phosphate, the exact mechanisms behind this regulatory function of NPP7 need to be addressed in future studies.
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