| 1. |
- Holmkvist, Petra, et al.
(author)
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A major population of mucosal memory CD4(+) T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality.
- 2015
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In: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 8:3, s. 545-558
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Journal article (peer-reviewed)abstract
- Mucosal tissues contain large numbers of memory CD4(+) T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4(+) T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα(+)DR3(+)CD4(+) T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα(+)DR3(+)CD4(+) T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα(+)DR3(+) CD4(+) T cells may contribute to antigen-independent innate responses at barrier surfaces.Mucosal Immunology advance online publication, 1 October 2014; doi:10.1038/mi.2014.87.
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| 2. |
- Holmkvist, Petra, et al.
(author)
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IL-18Rα-deficient CD4+ T cells induce intestinal inflammation in the CD45RBhi transfer model of colitis despite impaired innate responsiveness
- 2016
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In: European Journal of Immunology. - : Wiley. - 0014-2980. ; 46:6, s. 1371-1382
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Journal article (peer-reviewed)abstract
- IL-18 has been implicated in inflammatory bowel disease (IBD), however its role in the regulation of intestinal CD4+ T-cell function remains unclear. Here we show that murine intestinal CD4+ T cells express high levels of IL-18Rα and provide evidence that IL-18Rα expression is induced on these cells subsequent to their entry into the intestinal mucosa. Using the CD45RBhi T-cell transfer colitis model, we show that IL-18Rα is expressed on IFN-γ+, IL-17+, and IL-17+IFN-γ+ effector CD4+ T cells in the inflamed colonic lamina propria (cLP) and mesenteric lymph node (MLN) and is required for the optimal generation and/or maintenance of IFN-γ-producing cells in the cLP. In the steady state and during colitis, TCR-independent cytokine-induced IFN-γ and IL-17 production by intestinal CD4+ T cells was largely IL-18Rα−dependent. Despite these findings however, IL-18Rα−deficient CD4+ T cells induced comparable intestinal pathology to WT CD4+ T cells. These findings suggest that IL-18-dependent cytokine induced activation of CD4+ T cells is not critical for the development of T-cell-mediated colitis.
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| 3. |
- Holmkvist, Petra
(author)
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Regulation of T cell effector functions in the intestinal mucosa
- 2014
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Doctoral thesis (other academic/artistic)abstract
- T lymphocytes are a critical cellular component of the adaptive immune response. They are generated in the thymus from bone marrow derived progenitors, where they undergo commitment to the T cell lineage and differentiate and mature into naïve CD4+ and CD8+ T cells. Naïve CD4+ and CD8+ T cells activation takes place in lymphoid organs after recognition of cognate antigen in the context of major histocompatibility complex (MHC) molecules on antigen presenting cells (APCs). The effector functions of CD8+ T cells includes the MHC-I dependent recognition and lysis of target cells (e.g. virally infected cells) through the release of degranulating cytotoxic mediators but CD8+ T cells can also acquire suppressive functions (CD8+ regulatory T cells (Tregs). Activation of naïve CD4+ T cells leads to the generation of T helper cell subsets (Th, e.g. T helper (Th1), Th2, Th17 and CD4+ Tregs) and the type of Th cell that is generated during an immune response is largely dependent on the cytokine signals these cells receive during their initial activation in the lymph node.. The main function of CD4+ Th cells is to produce cytokines that that impact on the differentiation, recruitment and functionality of other immune and stromal cells, and as such these cells play a central role in shaping immune responses. Following an immune response some antigen-specific T cells remain as memory T cells. Memory T cells are long-lived and serve to protect us against re-infection with the same pathogen. The overall aim of this thesis was to study mechanisms regulating differentiation and functionality of intestinal CD4+ and CD8+ T cells. Memory CD4+ T cells is found in the circulation as well as in tissues. In addition to responding to re-infections in an antigen dependent manner these circulating memory CD4+ T cells can produce interferon (IFN)-γ in response to cytokines in the absence of T cell receptor (TCR) stimulation, suggesting that they may participate in immune responses in an innate-like manner. We could show that IL-15 or tumor necrosis factor (TNF)-like cytokine 1A(TL1a) induced production of IL-5, IL-6, IL-13, IL-22, granulocyte–macrophage colony-stimulating factor (GM-CSF), IFN-γ and TNF-α in a subset of memory CD4+ T cells co-expressing death receptor 3 (DR3) and IL-18Rα in presence of IL-12 and IL-18. TL1a synergized with IL-15 to further enhance the levels of all cytokines measured and the cytokine-induced cytokine production was severely diminished in the absence of IL-18. The intestine is a large reservoir of memory CD4+ T cells and we could show that a large proportion of these cells co-expressed IL-18Rα and DR3 in both humans and mice and these cells produced cytokines in response to cytokine stimulation. These results suggest that both human and murine memory IL-18Rα+DR3+ CD4+ T cells may contribute to antigen-independent innate-like responses in the intestine. We also found that CD4+ T cells expressing IL-18Rα and DR3 were present in the inflamed small intestine in patients with Crohn’s disease (CD), a chronic inflammatory disease that can affect all areas of the gastrointestinal tract, where theu co-localized with IL-18-expressing cells in intestinal lymphoid aggregates. This suggests that cytokine-activated CD4+ T cells might contribute to the high levels of proinflammatory cytokines observed in these patients. Bioactive IL-18 mRNA transcripts are increased in mucosal samples obtained from CD compared to controls. The role of IL-18 in intestinal inflammation has been thoroughly studied in various animal models of IBD and while most of these mice are protected from severe intestinal inflammation in absence of IL-18 there are also studies suggesting a protective role for IL-18. Although IL-18 is a pleotropic cytokine all of these studies was carried out by systemically blocking IL-18 signalling and did not take into account what cells that were affected. In the CD45RBhigh CD4+ T cell transfer model of IBD we could observe that all CD4+ T cells recovered from mesenteric lymph node and colon lamina propria (LP) expressed IL-18Rα in the setting of colitis. To identify a potential role of IL-18 signalling in CD4+ T cells ability to induce colitis in this model we transferred il-18r-/- CD45RBhighCD4+ T cells into rag-1-/- mice. The number of IFN-γ producing CD4+ T cells recovered from the colitic colon LP were significantly reduced compared to their wild type counterparts and il-18r-/- CD4+ T cells in the setting of colitis failed to produce cytokines in response to cytokine stimulation. Despite these findings il-18r-/- CD4+ T cells were equally proficient at inducing colitis as those CD4+ T cells from wild type mice. These results suggesting that IL-18 signaling in CD4+ T cells is not critical for their ability to drive disease pathology in the CD45RBhigh transfer model of colitis. The intestine is daily exposed to large amounts of antigens and is the major entry site for intracellular bacteria whose control requires the induction of protective CD8+ T cell responses. In the intestinal fatty acid-binding protein promoter truncated ovalbumin (iFABP-tOVA) mouse in which a surrogate antigen is expressed in the small intestinal epithelium we assessed mechanisms regulating mucosal CD8+ T cell priming and differentiation in the steady state and inflammatory setting. CD8+ T cells were found to differentiate into two distinct subsets, CD107a/b+ cytotoxic T cells (CTLs) and FoxP3+CD8+ T cells. FoxP3+CD8+ T cells but not CTLs required chemokine receptor 9 (CCR9) for effective homing to and expansion within the small intestinal mucosa. Further, we found that IRF8, but not IRF4, expression by intestinal dendritic cells (DCs) was critical for the development of the FoxP3+ subset in steady state but not the inflammatory setting. Collectively these findings broaden our understanding of the mechanisms regulating CD8+ T cell responses in the intestinal mucosa and have potential implications for mucosa vaccine design.
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| 4. |
- Joeris, Thorsten, et al.
(author)
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Intestinal cDC1 drive cross-tolerance to epithelial-derived antigen via induction of FoxP3+CD8+ Tregs
- 2021
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In: Science Immunology. - : American Association for the Advancement of Science (AAAS). - 2470-9468. ; 6:60
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Journal article (peer-reviewed)abstract
- Although CD8+ T cell tolerance to tissue-specific antigen (TSA) is essential for host homeostasis, the mechanisms underlying peripheral cross-tolerance and whether they may differ between tissue sites remain to be fully elucidated. Here, we demonstrate that peripheral cross-tolerance to intestinal epithelial cell (IEC)–derived antigen involves the generation and suppressive function of FoxP3+CD8+ T cells. FoxP3+CD8+ Treg generation was dependent on intestinal cDC1, whose absence led to a break of tolerance and epithelial destruction. Mechanistically, intestinal cDC1-derived PD-L1, TGFβ, and retinoic acid contributed to the generation of gut-tropic CCR9+CD103+FoxP3+CD8+ Tregs. Last, CD103-deficient CD8+ T cells lacked tolerogenic activity in vivo, indicating a role for CD103 in FoxP3+CD8+ Treg function. Our results describe a role for FoxP3+CD8+ Tregs in cross-tolerance in the intestine for which development requires intestinal cDC1.
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