Project description:In the present study we describe a new subset of murine T cells producing high levels of IL-10 that, in this case, are induced by C-type lectin receptor-stimulated (i.e., Dectin-1-stimulated) dendritic cells. This T cell produces IL-10 as a result of a transcriptional mechanism that is distinct from that inducing IL-10 in Th2 cells, Tr1 cells or other T cell subsets. In particular, the mechanism involves mTOR signaling and induction of the LIP isoform of C/EBPb, a factor that interacts with phospho-CREB and GATA3 to induce transactivation of the IL-10 gene. These T cells have strong regulatory properties in relation to fungal infection and hence have been termed Tr2 regulatory T cells to distinguish them from other regulatory T cell subsets.
Project description:ALK4R–Stimulated Glutaminolysis and mTOR-C/EBPbeta Signaling Drives the Differentiation of Novel IL-10-Producing Regulatory T Cells
Project description:Here we report that Dectin-1-stimulated dendritic cells (DCs) induce unique IL-10-producing T cells with strong regulatory function during fungal infection or experimental asthma.These T cells, which we call Dectin-10 T cells, are induced by DC-initiated signaling that sets in motion two complementary mechanisms of IL-10-producing T cell differentiation. The first involves induction of nascent Dect-10 T cell IL-4 synthesis and attendant GATA3 production, the latter a factor that exerts canonical and epigenetic transcriptional function at separate IL-10 promoter sites. The second involves TGFbetaR-family(ActRIB(ALK4)) signaling associated with induction of glutaminolysis and generation of alpha-ketoglutarate, a factor that induces rapamycin-sensitive TORC1 activation; the latter, in turn, causes translation of the LIP isoform of C/EBPbeta and binding LIP to CREB1 to form a CREB1-LIP complex that binds to adjacent sites on the IL- 10 promoter and transactivation of the IL10 gene. Dect-10 T cell regulatory function is manifest by its capacity to down-regulate normally protective immune responses to hyphal C. albicans renal infection. In addition, Dect-10 T cells, in accord with their IL-4-dependent genesis, suppress dust mite-induced experimental asthma.
Project description:IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3Neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3Neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease (IBD), demonstrate a deficiency in this specific regulatory T-cell subpopulation.
Project description:IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3Neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3Neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease (IBD), demonstrate a deficiency in this specific regulatory T-cell subpopulation.
Project description:IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3Neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3Neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease (IBD), demonstrate a deficiency in this specific regulatory T-cell subpopulation.
Project description:IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4+ T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3Neg CD4+ T cells that displays regulatory activity unlike other IL-10-producing CD4+ T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4+ T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3Neg CD4+ T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease (IBD), demonstrate a deficiency in this specific regulatory T-cell subpopulation.
Project description:Transcriptional repressor Prdm1/Blimp1 is known to play a key role in controlling B ells differentiation and regulating IL-10 production in regulatory T cells. B10 cells is the main IL-10 producing B cells in mouse spleen. We found that B10 cells and IL-10+ B cell levels are increased in Prdm1-deficient mice. Here, we compared the gene expression profiles of B10 cells from Prdm1-deficient mice (Cko) and its control littermate mice (Ctrl) in steady state and stimulated with anti-CD40 antibody for 48 h.
Project description:The ability of Treg-cells to produce interleukin-10 (IL-10) is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, only few Treg-cells produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregcells we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Treg-cells, which not only led to numeric expansion but also to a dramatic increase in IL- 10 production. IL-10 secreting Treg-cells strongly upregulated surface receptors associated with suppressive function, and had higher but IL-10 independent, in vitro suppressive capacity than nonproducing Treg-cells. Furthermore, polyclonally expanding Treg-cells shifted their migration receptor pattern after activation from a lymph node-seeking to an inflammation-seeking phenotype, explaining the preferential recruitment of IL-10 producers to sites of ongoing immune responses. Finally, we observed that IL-10 producing Treg-cells from CD28SA stimulated mice were more apoptosis-prone in vitro than their IL-10 negative counterparts. These findings support a model where prolonged activation of Treg-cells results in terminal differentiation towards an IL-10 producing effector phenotype associated with a limited lifespan, implicating built-in termination of immunosuppression.
Project description:In these experiments, we stimulated cytokine starved NK-92 cells with interleukin(IL)-2 or IL-15 for 0, 5, 10, 15, or 30 minutes and investigated the resulting phospho-signaling.