The intestinal micro-environment imprints stromal cells to promote efficient Treg induction in gut-draining lymph nodes.

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.

In vitro induced CD8+ regulatory T cells inhibit skin inflammation.

CD8(+) regulatory T cells appear impaired in number and/or function in some autoimmune diseases. However, the role of CD8(+) regulatory T cells in the pathogenesis of skin inflammation and psoriasis remains unknown. In this study, we set out to analyze the capability of CD8(+) regulatory T cells to inhibit skin inflammation in a murine model and to determine the frequency of CD8(+) regulatory T cells in patients with psoriasis. We demonstrate that murine fully competent CD8(+) regulatory T cells can be induced by stimulating naïve CD8(+) T cells in the presence of TGF-ß and retinoic acid (RA). Importantly, in vitro induced CD8(+) regulatory T cells significantly suppressed skin inflammation in vivo. Furthermore, we found that the frequency of regulatory CD8(+)CD25(+)Foxp3(+) T cells is decreased in peripheral blood but increased in lesional psoriatic skin of patients with psoriasis. Thus, our study suggests a previously unappreciated role of CD8(+)CD25(+)Foxp3(+) T cells in skin disorders, and induction of these cells in vitro may be an effective immunotherapy for skin inflammation.

CD4+Foxp3+ regulatory T cell expansion induced by antigen-driven interaction with intestinal epithelial cells independent of local dendritic cells.

BACKGROUND: Regulatory T cells (T(regs)) have potential anti-inflammatory effects and are likely to be important in the pathogenesis of chronic inflammatory bowel disease (IBD). However, the induction and expansion of T(regs) at sites of mucosal inflammation are not yet fully understood and may involve antigen presentation by local dendritic cells (DCs) and/or intestinal epithelial cells (IECs). METHODS: To determine the unique ways in which the gut induces or expands T(regs), a transgenic mouse model that is based on the specific expression of a model autoantigen (influenza haemagglutinin (HA)) in the intestinal epithelium (VILLIN-HA) was used. Gut-associated DCs and IECs isolated from these mice were phenotypically and functionally characterised for the potential to interact with HA-specific T(regs) in vitro and in vivo. RESULTS: Intestinal self-antigen expression leads to peripheral expansion of antigen-specific CD4(+)Foxp3(+) T(regs). Although gut-associated DCs can induce antigen-specific CD4(+)Foxp3(+) T cell proliferation, in vivo depletion of DCs did not preclude proliferation of these cells. Interestingly, antigen presentation by primary IECs is sufficient to expand antigen-specific CD4(+)Foxp3(+) T(regs) efficiently. This is dependent on major histocompatibility complex class II, but, in contrast to DCs, is unlikely to require transforming growth factor beta and retinoic acid. CONCLUSION: 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.