Epigenetic Imprinting of Tolerogenic Properties of Stromal Cells in Gut-Draining Lymph Nodes by Microenvironmental Factors

A fraction of regulatory T cells (Tregs) are de novo induced in the periphery from naïve precursor cells. These peripherally induced Tregs contribute to tolerance not only to the commensal microflora, but also to food-born antigens. Previous works of others and us has shown that the microenvironment of gut-draining lymph nodes (LN) promotes peripheral Treg induction by shaping the phenotype of non-hematopoietic LN stromal cells. In the present study, we have performed LN transplantations from different settings to unravel the contribution of stromal cells and environmental factors such as infection, chronic inflammation and antibiotic treatment to the high Treg-inducing capacity of gut-draining LN. BisSeq and RNASeq was carried out on stromal cells isolated from skin- and gut-draining LN of colonized vs. germ-free mice to identify genes that are epigenetically and transcriptionally controlled by location- as well as commensal-dependent factors. Our data provide evidence that LN stromal cells are shaped early and stably during ontogeny to contribute to the tolerogenic properties of gut-draining LN. Once established, the tolerogenic properties of gut-draining LN stromal cells are persistent even after infection or chronic inflammation. Thus, tolerogenic properties of stromal cells in gut-draining LN are stably imprinted by microenvironmental factors early during ontogeny.