Immune checkpoint function of T cell-derived CD70 in inflammatory T cell responses

Abstract

Abstract The CD27-CD70 pathway is known to provide a costimulatory signal with CD70 expressed on antigen-presenting cells while CD27 functioning on T cells. Although CD70 is also expressed on activated T cells, it remains unclear how T cell-derived CD70 affects T cell function. Therefore, we have assessed the role of T cell intrinsic CD70 using multiple models including autoimmune inflammatory bowel disease (IBD) and allogeneic graft-versus-host disease (GVHD). Compared with WT T cells, CD70−/− T cells surprisingly caused more severe IBD and GVHD and produced higher levels of inflammatory cytokines. Mechanistic analyses reveal that IFNg induces CD70 expression in T cells, and CD70 limits T cell expansion via a regulatory T cell-independent mechanism that involves caspase-dependent T cell apoptosis and upregulation of other immune checkpoint molecules. Overall, our findings demonstrate that T cell-derived CD70 plays a novel immune checkpoint role in inhibiting inflammatory T cell responses.