MERTK acts as a costimulatory receptor on human CD8+ T cells

The TAM family of receptor tyrosine kinases (TYRO3, AXL, and MERTK) is known to be expressed on antigen-presenting cells and function as oncogenic drivers and as inhibitors of inflammatory responses. Both human and mouse CD8 + T cells are thought to be negative for TAM receptor expression. In this study, we show that T-cell receptor (TCR)–activated human primary CD8 + T cells expressed MERTK and the ligand PROS1 from day 2 postactivation. PROS1-mediated MERTK signaling served as a late costimulatory signal, increasing proliferation and secretion of effector and memory-associated cytokines. Knockdown and inhibition studies confirmed that this costimulatory effect was mediated through MERTK. Transcriptomic and metabolic analyses of PROS1-blocked CD8 + T cells demonstrated a role of the PROS1–MERTK axis in differentiation of memory CD8 + T cells. Finally, using tumor-infiltrating lymphocytes (TIL) from melanoma patients, we show that MERTK signaling on T cells improved TIL expansion and TIL-mediated autologous cancer cell killing. We conclude that MERTK serves as a late costimulatory signal for CD8 + T cells. Identification of this costimulatory function of MERTK on human CD8 + T cells suggests caution in the development of MERTK inhibitors for hematologic or solid cancer treatment.