Intestinal CD4−CD8αβ−TCRαβ+ T cells function as tolerogenic antigen presenting cells in mice

The intestinal mucosa harbors diverse lymphocyte populations, including double negative CD4–CD8αβ–TCRαβ+ T (DNT) cells, in the intraepithelial compartment and the lamina propria. Here we report that DNT cells in mouse small intestines are motile and reach across the epithelial barrier to capture luminal antigens (Ags). DNT cells then migrate to mesenteric lymph nodes (MLN) and upregulate MHC-II, as evidenced by a sizeable fraction of mouse DNT cells in Peyer’s patches (PP) and MLN expressing MHC-II but little or no co-stimulatory molecules. Functionally, the presentation of intestinal antigens by DNT cells tolerizes antigen-specific naive CD4+ T cells, with this tolerization reversed by conditional ablation of MHC-II in T cells, thereby rendering mutant mice hypersusceptible to intestinal inflammation. Intriguingly, intestinal T cells in patients with Crohn’s disease also express lower levels of HLA-DR than those in healthy controls. Our findings thus potentially implicate MHC-II+ DNT cells in intestinal immune homeostasis and pathogenesis of inflammatory bowel disease.