CTLs play important roles in host immune responses to tumors. CD4 CTLs are characterized by their ability to secrete cytotoxic effector molecules, such as granzyme B and perforin, and kill target cells in a MHC class II–restricted manner. However, the cell surface markers of CD4 CTLs remain unknown, which hinders their separation and research on their function. In this study, we performed a bioinformatics analysis and experimental validation that revealed that G protein–coupled receptor 56 (GPR56) is a cell surface marker that can be used to characterize CD4 CTLs. We found that GPR56 and granzyme B were coexpressed in extremely high levels in human peripheral blood T cells, and that anti-GPR56 stimulation significantly upregulated the expression of granzyme B in both CD4+GPR56+ and CD8+GPR56+ T cells. These findings suggest that GPR56 expression and the GPR56 signaling pathway could contribute directly to the toxic function of either CD4+ or CD8+ T cells. We also used GPR56 as a biomarker to investigate the clinical significance of CD4 CTLs. GPR56+ T cell levels were increased in patients with lung cancer, and GPR56 expression was significantly correlated with lung cancer progression. A further analysis revealed an increase in exhausted cell states in lung cancer patients because of upregulation of programmed cell death protein 1 expression in GPR56+ T cells. The findings of this study suggest that GPR56 characterizes the cytotoxic states of either CD4+ or CD8+ T cells.

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