Analysis of the mechanisms that maintain intestinal regulatory T cells

Abstract Regulatory T cells (Tregs) play an important role maintaining intestinal homeostasis. The Treg pool from the small intestine lamina propria (siLP) include two subpopulations: Helios+ Tregs, comprised of mainly thymic derived Tregs, and the microbiota-induced RORgt+ Tregs. We used K14 transgenic mice lacking peripheral TCR-MHCII to examine the phenotype and maintenance of Helios+ Tregs in siLP. We find that the siLP of K14 mice fills with Helios+ Tregs that adopt an effector phenotype independent of TCR signaling. To dissect the mechanisms that maintain siLP Helios+ and RORgt+ siLP Treg subpopulations, we used blocking antibodies to inhibit costimulatory signals. We find that the composition of the Treg pool is dynamic; both subpopulations expand to compensate for the loss of the other to maintain intestinal Treg numbers. Moreover, we found that the balance between RORgt+ and Helios+ Tregs in siLP is differentially modulated by ICOS and CD28 signals. Thus, while Helios+ Tregs rely only on CD28 but neither ICOS nor MHCII signaling for their expansion; MHCII, CD28, and ICOS signaling play a role in RORgt+ Treg maintenance. Together, our data highlight the intricate signaling network that regulates the intestinal Treg homeostasis. Supported by grants from: AAI Careers in Immunology Fellowship VA NIH