CRT AM determines the CD4+ cytotoxic T lymphocyte lineage

Abstract

Naive T cells differentiate into various effector T cells, including CD4+ helper T cell subsets and CD8+ cytotoxic T cells (CTL). Although cytotoxic CD4+ T cells (CD4+CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4+ T cells that express class I-restricted T cell-associated molecule (CRT AM) upon activation possesses the characteristics of both CD4+ and CD8+ T cells. CRT AM+ CD4+ T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRT AM+ T cells are the precursor of CD4+CTL. Indeed, ectopic expression of CRT AM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4+CTL and IFN-γ production requires CRT AM-mediated intracellular signaling. CRT AM+ T cells traffic to mucosal tissues and inflammatory sites and developed into CD4+CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRT AM is critical to instruct the differentiation of CD4+CTL through the induction of Eomes and CTL-related gene.