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

Abstract

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.

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

“…1 Recent findings indicate that under homeostatic conditions, such peripherally induced Tregs (pTregs) are of functional importance mainly at feto-maternal interfaces and for maintaining tolerance to food-and microbiota-derived antigens at mucosal sites. [2][3][4][5][6] In addition to differences in ontogeny, there is growing evidence that Tregs having undergone antigen-specific stimulation may differ significantly from their naive recirculating counterparts in terms of activation status, migratory potential, and regulatory function. 7,8 Together with the notion that Tregs having different origins or anatomical locations display distinct but specific gene expression profiles, 9 this has led to the discovery of different functional Treg subpopulations, termed ''effector'' Treg lineages.…”

Fibroblastic Reticular Cells: Organization and Regulation of the T Lymphocyte Life Cycle

“…As such, this system has provided a useful tool for investigating location-specific properties that are intrinsic to stroma. The capacity of LN stroma to induce the generation of de novo regulatory T cells (Tregs) was explored in a recent study (56) in which liver draining celiac LNs and gut-draining mesenteric LNs were transplanted into the popliteal fossa after excision of the endogenous popliteal LN. When compared to transplanted popliteal LN controls, celiac and mesenteric LNs represented a significantly superior environment for de novo Treg differentiation from adoptively transferred naïve Foxp3 − CD4 + OTII T cells (56).…”

Emerging roles of lymphatic endothelium in regulating adaptive immunity

“…In that study, it was suggested that stimuli derived from the gut microbiota enable LNSCs to modulate tolerogenic properties of DCs (75).…”