The human small intestine comprises two subsets of regulatory Foxp3+ CD4 T cells with very different life span and functional properties

ABSTRACTGut resident regulatory CD4+ T (Tregs) cells in mice are mainly specific for intestinal antigens and play an important role in the suppression of immune responses against harmless dietary antigens and the gut microbiota. In contrast, information about the phenotype and function of Tregs in the human gut is limited. Here, we performed a detailed characterization of Foxp3+ CD4 Tregs in human small intestine (SI). SI Foxp3+ CD4 T cells were CD45RA-CTLA4+CD127- and suppressed proliferation of autologous T cells. Approximately 60% of SI Tregs expressed the transcription factor Helios. When stimulated, Helios- Tregs produced IL-17, IFNγ and IL-10, whereas Helios+ Tregs produced very low levels of these cytokines. Sampling mucosal tissue from transplanted human duodenum we demonstrated that donor SI Helios+ Tregs have a rapid turnover rate whereas Helios- Tregs persisted for at least 1 yr post transplantation. In the normal SI, Foxp3+ Tregs constituted only 2% of all CD4 T cells, while in active celiac disease both subsets expanded 5-10-fold. Taken together, these findings suggest that human SI contains two phenotypically and functionally distinct Treg subsets (Helios+ and Helios- Tregs), which are reminiscent of rapidly renewed dietary antigen-specific Tregs and microbiota-specific Tregs resident in the mouse gut, respectively.