The intestinal lamina propria is a unique niche for regulatory T cells

Abstract

Foxp3⁺ regulatory T cells (Tregs) are critical to mantain intestinal homeostasis. Like all CD4⁺ T cells, Tregs require TCR-MHCII interactions for their development in thymus and differentiation in periphery. Past studies suggest that the TCR repertoire of intestinal lamina propria (siLP) Tregs is skewed towards food and commensal bacteria antigens. However, by using a transgenic mouse model that lacks peripheral MHCII expression and peripheral Tregs induction (K14 mice), we have demonstrated that thymically generated Tregs could enter to the siLP of weanlings and proliferate independently of MHCII to fill and maintain the compartment.

Newly-generated Tregs egress from thymus as central Tregs and acquire an effector phenotype after TCR signals in periphery. However, despite the lack of MHCII in the siLP, K14 Tregs are activated and phenotypically similar to effector Tregs in WT siLP. Interestingly, transcriptional profiling reveals that many components of a TCR-dependent expression module are present in both K14 and WT siLP Tregs. Furthermore, differently to splenic Tregs, K14 siLP Tregs highly express Nur77 and IRF4, often regulated through TCR signaling.

Tregs from K14 siLP localize mainly at isolated lymphoid follicles, where they are in proximity to B cells and dendritic cells; suggesting that siLP Tregs may still receive MHCII-independent signals from APCs, perhaps via costimulation molecules and/or paracrine cytokine stimulation. Indeed a short-term costimulation blockade with CTLA4-Ig reduces Nur77 expression on K14 siLP Tregs.

Taken together, these results suggest that the intestinal microenvironment uniquely maintains the differentiation and homeostasis of effector Tregs independent of MHCII-TCR interactions.