To examine the origin of intestinal mucosal T cells and, in particular, unconventional CD8αα+ T cells, we have undertaken a thorough analysis of the gut immune compartment in euthymic and athymic mice carrying either wild-type or mutant transcription factor retinoic acid-related orphan receptor-γt (RORγt). We identified a previously unrealized complexity of gut cryptopatch (CP) cells that challenges the previous assertion that CP cells comprise RORγt-expressing adult counterparts of fetal lymphoid tissue inducer (Lti) cells. We showed that many CP cells express intermediate T cell differentiation markers, whether or not they express RORγt, and found that CPs are not completely dependent on RORγt, as previously reported, but merely fewer in number in the RORγt-deficient condition. Indeed, c-kit+ IL-7R+ Lin-RORγt- cells inside the CP and c-kit+IL-7R+Lin- RORγt- and c-kit+IL-7R+ Lin-RORγtlow cells outside the CP basically remain in the gut mucosa of RORγt-deficient RORγtEGFP/EGFP mice. Consistent with these non-Lti-like c-kit+ IL-7R+Lin- cells being gut T cell progenitors, RORγt-deficient mice develop the normal number of intestinal mucosal T cells. These results clearly reassert the intraintestinal differentiation of the body's largest peripheral T cell subpopulation.
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