Triggering of TNFRSF25 promotes CD8+ T‐cell responses and anti‐tumor immunity

TNFRSF25 is a member of the TNF receptor superfamily (TNFRSF) that binds to the TNF‐like protein TL1A. Although recent studies have demonstrated a role for TNFRSF25 in regulating CD4+ T‐cell responses, it remains to be determined if TNFRSF25 functions as a costimulatory receptor for CD8+ T cells. Here, we demonstrate that ectopic expression of TL1A on mouse plasmacytomas promotes elimination of tumor cells in a CD8+ T‐cell‐dependent manner and renders mice immune to a subsequent challenge with tumor cells. To gain further insight into the role of TNFRSF25 in CD8+ T‐cell responses, we analyzed the effect of TNFRSF25 triggering on OT‐I TCR transgenic T cells. We demonstrate that TNFRSF25 triggering in vivo with soluble TL1A promotes the proliferation and accumulation of antigen‐specific CD8+ T cells as well as their differentiation into CTLs. Furthermore, we show that TNFRSF25 also functions as a costimulatory receptor for memory CD8+ T cells. Thus, TNFRSF25 triggering enhances the secondary expansion of endogenous antigen‐specific memory CD8+ T cells. Our data suggest that TNFRSF25 agonists, such as soluble TL1A, could potentially be used to enhance the immunogenicity of vaccines that aim to elicit human anti‐tumor CD8+ T cells.