1. ¹Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
2. ²Department of Biochemistry and Integrative Medical Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
3. ³Department of Dermatology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
4. ⁴Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

Correspondence: H Ishikawa, (h-ishika@sc.itc.keio.ac.jp)

Received 26 November 2007; Accepted 25 January 2008.

Abstract

To examine the origin of intestinal mucosal T cells and, in particular, unconventional CD8⁺ 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-t (RORt). We identified a previously unrealized complexity of gut cryptopatch (CP) cells that challenges the previous assertion that CP cells comprise RORt-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 RORt, and found that CPs are not completely dependent on RORt, as previously reported, but merely fewer in number in the RORt-deficient condition. Indeed, c-kit⁺IL-7R⁺Lin^-RORt^- cells inside the CP and c-kit⁺IL-7R⁺Lin^-RORt^- and c-kit⁺IL-7R⁺Lin^-RORt^low cells outside the CP basically remain in the gut mucosa of RORt-deficient RORt^EGFP/EGFP mice. Consistent with these non-Lti-like c-kit⁺IL-7R⁺Lin^- cells being gut T cell progenitors, RORt-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.