MERTK Acts as a costimulatory receptor on human cd8 t cells
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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.
Originalsprog | Engelsk |
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Tidsskrift | Cancer Immunology Research |
Vol/bind | 7 |
Udgave nummer | 9 |
Sider (fra-til) | 1472-1484 |
Antal sider | 13 |
ISSN | 2326-6066 |
DOI | |
Status | Udgivet - 2019 |
ID: 227470415