Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid

TLDR

The intestinal immune system maintains homeostasis through redundant regulatory strategies and harbors many Foxp3+ regulatory T cells. The study hypothesizes that the gut environment preferentially supports extrathymic development of regulatory T cells. Peripheral conversion of CD4+ T cells to regulatory T cells mainly occurs in gut‑associated lymphoid tissue after oral antigen exposure and lymphopenia, with lamina propria dendritic cells driving high conversion via TGF‑β and retinoic acid, demonstrating that the intestinal immune system promotes de novo regulatory T cell generation.

Abstract

To maintain immune homeostasis, the intestinal immune system has evolved redundant regulatory strategies. In this regard, the gut is home to a large number of regulatory T (T reg) cells, including the Foxp3+ T reg cell. Therefore, we hypothesized that the gut environment preferentially supports extrathymic T reg cell development. We show that peripheral conversion of CD4+ T cells to T reg cells occurs primarily in gut-associated lymphoid tissue (GALT) after oral exposure to antigen and in a lymphopenic environment. Dendritic cells (DCs) purified from the lamina propria (Lp; LpDCs) of the small intestine were found to promote a high level of T reg cell conversion relative to lymphoid organ–derived DCs. This enhanced conversion by LpDCs was dependent on TGF-β and retinoic acid (RA), which is a vitamin A metabolite highly expressed in GALT. Together, these data demonstrate that the intestinal immune system has evolved a self-contained strategy to promote T reg cell neoconversion.