Studies on the roles of intestinal CX3CR1 cells for induction of CD103+ regulatory T cells

Abstract

Foxp3+ regulatory T cells (Tregs) are critical for the maintenance of mucosal tolerance as well as the regulation of inflammation in the gut. In this study, I show that in the presence of high dose antigens, intestinal CX3CR1+ cells promoted differentiation of Tregs and potentiated Foxp3 upregulation during their proliferation. Interestingly, intestinal CX3CR1+ cells, but not CX3CR1- cells, sustained their ability to promote Tregs under CpG-stimulated conditions. Additionally, I found that the proportion of CD103+ Tregs was elevated in the gut-associated lymphoid tissues, particularly in the small intestine, in a manner partially dependent on the MyD88 signaling pathway. Using in vitro co-culture, I found that intestinal CX3CR1+ cells induced more CD103+ Tregs than CX3CR1- cells in an IL-10-dependent manner. Importantly, the CD103+ Tregs reduced the incidence of diarrhea in a mouse food allergy model. Interestingly, the majority of induced Tregs (iTregs) generated by intestinal CXCR1+ cells expressed Helios in a TNF-α-dependent manner, thus giving rise to the induction of CD103+Helios+ Tregs that were abundant in the small intestine. Taken together, intestinal CX3CR1+ cells are able to induce a phenotypically unique population of CD103 and Helios-expressing Treg under inflammatory conditions. Thus, my results identify CX3CR1+ cells as major antigen presenting cells for Treg homeostasis in the gut during inflammation.