| 1. |
- Hagberg, Niklas, et al.
(författare)
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Systemic Lupus Erythematosus Immune Complexes Increase the Expression of SLAM Family Members CD319 (CRACC) and CD229 (LY-9) on Plasmacytoid Dendritic Cells and CD319 on CD56(dim) NK Cells
- 2013
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 191:6, s. 2989-2998
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Tidskriftsartikel (refereegranskat)abstract
- Patients with systemic lupus erythematosus (SLE) display an activated type I IFN system due to unceasing IFN-a release from plasmacytoid dendritic cells (pDCs) stimulated by nucleic acid-containing immune complexes (ICs). NK cells strongly promote the IFN-a production by pDCs; therefore, we investigated surface molecules that could be involved in the pDC-NK cell cross-talk. In human PBMCs stimulated with RNA-containing ICs (RNA-ICs), the expression of the signaling lymphocyte activation molecule (SLAM) family receptors CD319 and CD229 on pDCs and CD319 on CD56(dim) NK cells was selectively increased. Upregulation of CD319 and CD229 on RNA-IC-stimulated pDCs was induced by NK cells or cytokines (e. g., GM-CSF, IL-3). IFN-alpha-producing pDCs displayed a higher expression of SLAM molecules compared with IFN-a 2 pDCs. With regard to signaling downstream of SLAM receptors, pDCs expressed SHIP-1, SHP-1, SHP-2, and CSK but lacked SLAM-associated protein (SAP) and Ewing's sarcoma-activated transcript 2 (EAT2), indicating that these receptors may act as inhibitory receptors on pDCs. Furthermore, pDCs from patients with SLE had decreased expression of CD319 on pDCs and CD229 on CD56 dim NK cells, but RNA-IC stimulation increased CD319 and CD229 expression. In conclusion, this study reveals that the expression of the SLAM receptors CD319 and CD229 is regulated on pDCs and NK cells by lupus ICs and that the expression of these receptors is specifically altered in SLE. These results, together with the observed genetic association between the SLAM locus and SLE, suggest a role for CD319 and CD229 in the SLE disease process.
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| 2. |
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| 3. |
- Kokkinou, Efthymia, et al.
(författare)
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The single-cell transcriptional landscape of innate and adaptive lymphocytes in pediatric-onset colitis
- 2023
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Ingår i: Cell reports medicine. - 2666-3791. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- Innate lymphoid cells (ILCs) are considered innate counterparts of adaptive T cells; however, their common and unique transcriptional signatures in pediatric inflammatory bowel disease (pIBD) are largely unknown. Here, we report a dysregulated colonic ILC composition in pIBD colitis that correlates with inflammatory ac-tivity, including accumulation of naive-like CD45RA+CD62L- ILCs. Weighted gene co-expression network analysis (WGCNA) reveals modules of genes that are shared or unique across innate and adaptive lympho-cytes. Shared modules include genes associated with activation/tissue residency, naivety/quiescence, and antigen presentation. Lastly, nearest-neighbor-based analysis facilitates the identification of most in-flamedand least inflamedlymphocytes in pIBD colon with unique transcriptional signatures. Our study reveals shared and unique transcriptional signatures of colonic ILCs and T cells in pIBD. We also provide insight into the transcriptional regulation of colonic inflammation, deepening our understanding of the poten-tial mechanisms involved in pIBD.
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| 5. |
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| 6. |
- Rao, Anna, et al.
(författare)
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Cytokines regulate the antigen-presenting characteristics of human circulating and tissue-resident intestinal ILCs
- 2020
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- ILCs and T helper cells have been shown to exert bi-directional regulation in mice. However, how crosstalk between ILCs and CD4(+) T cells influences immune function in humans is unknown. Here we show that human intestinal ILCs co-localize with T cells in healthy and colorectal cancer tissue and display elevated HLA-DR expression in tumor and tumor-adjacent areas. Although mostly lacking co-stimulatory molecules ex vivo, intestinal and peripheral blood (PB) ILCs acquire antigen-presenting characteristics triggered by inflammasome-associated cytokines IL-1 beta and IL-18. IL-1 beta drives the expression of HLA-DR and co-stimulatory molecules on PB ILCs in an NF-kappa B-dependent manner, priming them as efficient inducers of cytomegalovirus-specific memory CD4(+) T-cell responses. This effect is strongly inhibited by the anti-inflammatory cytokine TGF-beta. Our results suggest that circulating and tissue-resident ILCs have the intrinsic capacity to respond to the immediate cytokine milieu and regulate local CD4(+) T-cell responses, with potential implications for anti-tumor immunity and inflammation. Murine ILCs can modulate T cell responses in MHCII-dependent manner. Here the authors show that human ILCs process and present antigens and induce T-cell responses upon exposure to IL-1-family cytokines; along with the article by Lehmann et al, this work elucidates how cytokines set context specificity of ILC-T cell crosstalk by regulating ILC antigen presentation.
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| 7. |
- Schlums, Heinrich
(författare)
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Human cytotoxic lymphocyte differentiation in health and disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cytotoxic lymphocytes, comprising natural killer (NK) cells and CD8+ cytotoxic T cells, eradicate infected or malignant cells by release of lytic granules and alarm the immune system through production of pro-inflammatory cytokines and chemokines. NK cells and CD8+ T cells belong to different arms of the immune system, employing complementary strategies for target cell recognition. As part of the innate arm, NK cells sense missing or induced self-molecules by an array of germline-encoded activating and inhibitory cell surface receptors. In contrast, adaptive CD8+ T cells depend on somatically recombined, clonally distributed T cell receptors (TCR) that recognize unique foreign peptides presented by MHC class I on target cells. Importantly, while mature NK cells readily kill target cells without prior sensitization, naive CD8+ T cells require antigen priming to differentiate into cytotoxic effector and long-lived memory cells, providing long-term protection against re-infection. Recently, memory features including longevity and recall responses have also been ascribed to differentiated NK cell subsets. The work presented in my thesis contributes to our molecular understanding of cytotoxic lymphocyte differentiation processes in health and disease. Exocytosis of lytic granules containing cytotoxic cargo is tightly controlled, but the transcriptional regulation of the factors governing degranulation is poorly understood. In paper I, we found that expression of one of those factors, Munc13-4, was induced upon cytotoxic lymphocyte maturation and required cooperative binding of the transcription factors ELF1 and STAT4 to an evolutionary conserved region in intron 1. Transcription factor-binding facilitated chromatin remodeling and DNA accessibility, allowing for enhanced transcription of the conventional as well as induction of a newly identified, alternative Munc13-4 isoform that is likely to play a central role in lymphocyte cytotoxicity. Infection with cytomegalovirus (CMV) in mice and man is associated with expansion and persistence of NK cell subsets with enhanced effector function. In paper II, we show that such adaptive NK cells display previously unappreciated phenotypic and functional heterogeneity, and provide a molecular definition of such diverse subsets. Human adaptive NK cells lacked expression of the intracellular signaling molecules FcεRγ, SYK and EAT-2 as well as the transcription factor PLZF, thereby altering the signaling properties of key NK cell surface receptors and the responsiveness to innate cytokines, respectively. Silencing of signaling protein expression correlated with promoter DNA methylation and global DNA methylation patterns of adaptive NK cells approximated those of differentiated CD8+ cytotoxic effector T cells. Importantly, adaptive NK cells failed to kill activated, autologous T cells, implying a functional specialization towards immunosurveillance of infected cells. Moreover, utilizing samples from patients with bone marrow disorders associated with GATA2 haploinsufficiency (paper III) or acquired PIGA mutations in hematopoietic stem cells (paper IV), we demonstrate that adaptive NK cells are long-lived and can persist in settings of hematopoietic stem and progenitor cell attrition where canonical NK cells are lost. Tissue-resident memory T (TRM) cells provide early, localized adaptive immunity in nonlymphoid tissues. In paper V, we discovered a functional dichotomy of CD8+ skin TRM cells based on expression of the marker CD49a. Upon stimulation, CD49a+ cells produced IFN-γ and acquired cytotoxic potential by induction of the lytic granule constituents perforin and granzyme B. Primed CD49a+ T cells accumulated in the dermis and epidermis of vitiligo lesions, an autoimmune condition characterized by local depigmentation as a result of melanocyte destruction. In contrast, CD49a– T cells produced IL-17 and were enriched in lesional skin from psoriasis patients, promoting local inflammation. These insights shed light on novel mechanisms controlling human cytotoxic lymphocyte differentiation and may thus be of potential benefit to health.
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| 8. |
- Zitti, Beatrice, et al.
(författare)
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Human skin-resident CD8+T cells require RUNX2 and RUNX3 for induction of cytotoxicity and expression of the integrin CD49a
- 2023
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Ingår i: Immunity. - : CELL PRESS. - 1074-7613 .- 1097-4180. ; 56:6, s. 1285-1302.e7
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Tidskriftsartikel (refereegranskat)abstract
- The integrin CD49a marks highly cytotoxic epidermal-tissue-resident memory (TRM) cells, but their differen-tiation from circulating populations remains poorly defined. We demonstrate enrichment of RUNT family tran-scription-factor-binding motifs in human epidermal CD8+CD103+CD49a+ TRM cells, paralleled by high RUNX2 and RUNX3 protein expression. Sequencing of paired skin and blood samples revealed clonal overlap be-tween epidermal CD8+CD103+CD49a+ TRM cells and circulating memory CD8+CD45RA-CD62L+ T cells. In vitro stimulation of circulating CD8+CD45RA-CD62L+ T cells with IL-15 and TGF-b induced CD49a expres-sion and cytotoxic transcriptional profiles in a RUNX2-and RUNX3-dependent manner. We therefore identi-fied a reservoir of circulating cells with cytotoxic TRM potential. In melanoma patients, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8+CD103+CD49a+ TRM cell signature and improved pa-tient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differ-entiation of cytotoxic CD8+CD103+CD49a+ TRM cells, providing immunosurveillance of infected and malig-nant cells.
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