Background/Purpose: Regulatory T cells (Tregs) are critical to prevent autoimmune diseases such as inflammatory bowel disease and rheumatoid arthritis.  Like all CD4+ T cells, CD4+ Tregs expressing the transcription factor Foxp3 develop in the thymus, though Tregs also are generated in the periphery from naïve CD4+ T cells. T cell receptor (TCR)-major histocompatibility complex class II (MHC II) signals are necessary for thymic Treg generation and provide antigen-specific signals in the periphery.  Yet the role of MHC II signals in peripheral Treg maintenance has remained unclear, or in cases of tissue sites such as intestine, unstudied. 

Methods: To dissect the role of MHC II in intestinal Treg maintenance, we examined K14/Abb (K14) mice that have MHC II restricted to cortical thymic epithelium but lack peripheral TCR-MHC II interactions. 

Results: Intestinal Treg frequency was increased in mice lacking peripheral expression of MHCII. Treg proliferation was equivalent in the intestinal lamina propria of young K14 and wild type mice; however, proliferation of conventional T cells was MHC II-dependent.  The initial MHC II-independent Treg accumulation was not due to increased homing directly from the thymus, as intestinal Tregs in young K14 mice were not enriched for recent thymic emigrants (RTEs). Intestinal Tregs were maintained in adult K14 mice when, in contrast to young mice, Treg and Tconv proliferation and turnover were similar to wild type.  In all adult mice the intestine contained no Treg RTEs.  However, depletion of microbial gut flora by antibiotics in adult K14 mice partially restored the Treg frequency to wild type levels.

Conclusion: These data suggest that the intestine specifically contains a niche for regulatory T cells that does not require MHC II signals to be filled, but may rely on MHC II-independent, intestinal flora-derived signals to be subsequently maintained.  These cells may represent a tissue-specific mechanism to prevent autoimmunity.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/mhc-ii-independent-regulation-of-intestinal-tregs/