The Development of Colitogenic CD4+ T Cells Is Regulated by IL-7 in Collaboration with NK Cell Function in a Murine Model of Colitis

Abstract

We previously reported that IL-7−/−RAG−/− mice receiving naive T cells failed to induce colitis. Such abrogation of colitis may be associated with not only incomplete T cell maintenance due to the lack of IL-7, but also with the induction of colitogenic CD4+ T cell apoptosis at an early stage of colitis development. Moreover, NK cells may be associated with the suppression of pathogenic T cells in vivo, and they may induce apoptosis of CD4+ T cells. To further investigate these roles of NK cells, RAG−/− and IL-7−/−RAG−/− mice that had received naive T cells were depleted of NK cells using anti-asialo GM1 and anti-NK1.1 Abs. NK cell depletion at an early stage, but not at a later stage during colitogenic effector memory T cell (TEM) development, resulted in exacerbated colitis in recipient mice even in the absence of IL-7. Increased CD44+CD62L− TEM and unique CD44−CD62L− T cell subsets were observed in the T cell-reconstituted RAG−/− recipients when NK cells were depleted, although Fas, DR5, and IL-7R expressions in this subset differed from those in the CD44+CD62L− TEM subset. NK cell characteristics were the same in the presence or absence of IL-7 in vitro and in vivo. These results suggest that NK cells suppress colitis severity in T cell-reconstituted RAG−/− and IL-7−/−RAG−/− recipient mice through targeting of colitogenic CD4+CD44+CD62L− TEM and, possibly, of the newly observed CD4+CD44−CD62L− subset present at the early stage of T cell development.