Gut-draining mesenteric lymph nodes (mLNs) are important for inducing peripheral tolerance towards food and commensal antigens by providing an optimal microenvironment for de novo generation of Foxp3+ regulatory T cells (Tregs). We previously identified microbiota-imprinted mLN stromal cells as a critical component in tolerance induction. Here we show that this imprinting process already takes place in the neonatal phase, and renders the mLN stromal cell compartment resistant to inflammatory perturbations later in life. LN transplantation and single-cell RNA-seq uncover stably imprinted expression signatures in mLN fibroblastic stromal cells. Subsetting common stromal cells across gut-draining mLNs and skin-draining LNs further refine their location-specific immunomodulatory functions, such as subset-specific expression of Aldh1a2/3. Finally, we demonstrate that mLN stromal cells shape resident dendritic cells to attain high Treg-inducing capacity in a Bmp2-dependent manner. Thus, crosstalk between mLN stromal and resident dendritic cells provides a robust regulatory mechanism for the maintenance of intestinal tolerance.

De novo induction of Foxp3⁺ regulatory T cells (Tregs) is particularly efficient in gut-draining mesenteric and celiac lymph nodes (mLN and celLN). Here we used LN transplantations to dissect the contribution of stromal cells and environmental factors to the high Treg-inducing capacity of these LN. After transplantation into the popliteal fossa, mLN and celLN retained their high Treg-inducing capacity, whereas transplantation of skin-draining LN into the gut mesenteries did not enable efficient Treg induction. However, de novo Treg induction was abolished in the absence of dendritic cells (DC), indicating that this process depends on synergistic contributions of stromal and DC. Stromal cells themselves were influenced by environmental signals as mLN grafts taken from germ-free donors and celLN grafts taken from vitamin A-deficient donors did not show any superior Treg-inducing capacity. Collectively, our observations reveal a hitherto unrecognized role of LN stromal cells for the de novo induction of Foxp3⁺ Tregs.

Regulatory T cells (Treg) are supportive to cancer development in most tissues, but their role in colitisassociated colon cancer (CAC) remains unclear. In this study, we investigated the role of CD4

This study provides experimental evidence for a new concept in mucosal immunity: in contrast to current thinking, expansion of T(regs) can be achieved independently of local DCs through antigen-specific IEC-T cell interactions.

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Compelling evidence demonstrates that intestinal commensal microbiota modulate conventional and regulatory T cell (Treg) responses that are required for effective host defence against pathogens and avoidance of autoimmunity and other immunopathologic conditions. Here, we investigated the contribution of the commensal microbiota and Toll-like receptor (TLR) signaling to homeostasis of Foxp3− conventional CD4 + T cells and Foxp3 + Tregs. Upon long-term antibiotics treatment, we observed a significant reduction of conventional CD4 + T cell proliferation in a systemic manner, whereas Foxp3 + Treg proliferation was locally impaired in gut-draining mesenteric lymph nodes and Peyer's patches. The proliferative response to microbial components was not mediated by TLRs as MyD88-and various TLR-deficient mice displayed normal or even increased conventional T cell and Foxp3 + Treg proliferation. Thus, commensal microbiota-derived stimuli support cycling of both conventional CD4 + T cells and Foxp3 + Tregs with TLR-mediated recognition of bacterial components not being the major mechanism controlling microbiota-driven T cell homeostasis.

BackgroundIn contrast to intestinal CD4+ regulatory T cells (Tregs), the generation and function of immunomodulatory intestinal CD8+ T cells is less well defined. To dissect the immunologic mechanisms of CD8+ T cell function in the mucosa, reactivity against hemagglutinin (HA) expressed in intestinal epithelial cells of mice bearing a MHC class-I-restricted T-cell-receptor specific for HA was studied.Methodology and Principal FindingsHA-specific CD8+ T cells were isolated from gut-associated tissues and phenotypically and functionally characterized for the expression of Foxp3+ and their suppressive capacity. We demonstrate that intestinal HA expression led to peripheral induction of HA-specific CD8+Foxp3+ T cells. Antigen-experienced CD8+ T cells in this transgenic mouse model suppressed the proliferation of CD8+ and CD4+ T cells in vitro. Gene expression analysis of suppressive HA-specific CD8+ T cells revealed a specific up-regulation of CD103, Nrp1, Tnfrsf9 and Pdcd1, molecules also expressed on CD4+ Treg subsets. Finally, gut-associated dendritic cells were able to induce HA-specific CD8+Foxp3+ T cells.Conclusion and SignificanceWe demonstrate that gut specific antigen presentation is sufficient to induce CD8+ Tregs in vivo which may maintain intestinal homeostasis by down-modulating effector functions of T cells.