Classical Th1 Cells Obtain Colitogenicity by Co-existence of RORγt-expressing T Cells in Experimental Colitis

Background: Both Th1 and Th17 cell types are involved in the pathogenesis of chronic intestinal inflammation. We recently demonstrated that retinoid-related orphan receptor gamma t (ROR gamma t)-expressing Th17 cells are progenitor cells for alternative Th1 cells, which have the potential to induce colitis. However, the involvement of classical Th1 (cTh1) cells generated directly from naive T cells without ROR gamma t expression in the pathogenesis of colitis remains poorly understood. Methods: We performed a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of splenic CD4(+)CD45RB(high) T cells obtained from wild-type, ROR gamma t(gfp/gfp), or ROR gamma t(gfp/+) mice into RAG-2(-/-) mice. Results: RAG-2(-/-) mice receiving transfer of in vitro-manipulated ROR gamma t(gfp/gfp) Th1 cells developed colitis. RAG-2(-/-) mice co-transferred with splenic CD4+CD45RB(high) T cells obtained from wild-type mice and ROR gamma t(gfp/gfp) mice developed colitis with a significant increase in ROR gamma t(gfp/gfp) cTh1 cell numbers when compared with noncolitic mice transferred with splenic CD4(+)CD45RB(high) T cells obtained from ROR gamma t(gfp/gfp) mice. Furthermore, RAG-2(-/-) mice transferred with in vivo-manipulated ROR gamma tg(fp/gfp) cTh1 cells developed colitis with a significant increase in ROR gamma t(gfp/gfp) cTh1 cell numbers. Conclusions: These findings indicate that both alternative Th1 cells and cTh1 cells have the potential to be colitogenic in an adaptive transfer model. The development of cTh1 cells was dependent on the co-existence of ROR gamma t-expressing T cells, suggesting a critical role for the interactions of these cell types in the development of chronic intestinal inflammation.