Analysis of tissue specific mechanisms that control the maintenance of Foxp3+ regulatory T cells in the intestine

Abstract

Abstract Our lab studies the tissue specific pathways implicated in the maintenance of intestinal Foxp3+ regulatory T cells (Tregs). Previously we used K14 transgenic mice lacking peripheral TCR-MHCII to show that the small intestine lamina propria (siLP) is a niche for natural Tregs that can be filled and maintained independently of Ag-specific signals. K14 siLP Tregs display an effector phenotype (CD62loCD44hiCD103+ICOS+) similar to WT. Effector Tregs are known to be largely peripheral tissue-resident cells that require continued TCR and costimulatory signals for their maintenance. In contrast, we find that in K14 mice the blockade of the CTLA4/CD28—but not ICOS—pathway reduces the proliferation of siLP Tregs while preserving their effector phenotype (CD62loCD44hi). Thus, our results suggest that a population of thymically derived effector Tregs that depend on costimulatory signals can be maintained in the siLP independently of Ag-specific signals. B7-1/B7-2 and CD28/CTLA4 are cell surface molecules that interact through cell-cell contact. By microscopic analyses we show that a population of siLP Tregs localize inside of organized lymphoid structures known as isolated lymphoid follicles (ILF). B cells are the largest lymphocyte population within ILFs. Interestingly, our preliminary data suggest that B cells play a role in maintaining siLP Tregs in steady state, as the depletion of B cells with Rituximab reduces Treg numbers in the intestine of huCD20 mice. Additional imaging studies show ILF Tregs in intimate contact with B cells, suggesting that B cells might influence Tregs numbers by a cell-cell contact dependent mechanism. Thus, our data highlight the intricate signaling network that regulates intestinal Treg homeostasis.