NK cells and CD8 T cells use cytotoxic molecules to kill virally infected and tumor cell targets. While perforin and granzyme B (GzmB) are the most commonly studied lytic molecules, less is known about granzyme K (GzmK). However, this granzyme has been recently associated with improved prognosis in solid tumors. In this study, we show that, in humans, GzmK is predominantly expressed by innate-like lymphocytes, as well as a newly identified population of GzmK+CD8+ non– mucosal-associated invariant T cells with innate-like characteristics. We found that GzmK+ T cells are KLRG1+EOMES+IL-7R+CD62LTcf7int, suggesting that they are central memory T and effector memory T cells. Furthermore, GzmK+ cells are absent/low in cord blood, suggesting that GzmK is upregulated with immune experience. Surprisingly, GzmK+ cells respond to cytokine stimuli alone, whereas TCR stimulation downregulates GzmK expression, coinciding with GzmB upregulation. GzmK+ cells have reduced IFN-γ production compared with GzmB+ cells in each T cell lineage. Collectively, this suggests that GzmK+ cells are not naive, and they may be an intermediate memory-like or preterminally differentiated population. GzmK+ cells are enriched in nonlymphoid tissues such as the liver and adipose. In colorectal cancer, GzmK+ cells are enriched in the tumor and can produce IFN-γ, but GzmK+ expression is mutually exclusive with IL-17a production. Thus, in humans, GzmK+ cells are innate memory-like cells that respond to cytokine stimulation alone and may be important effector cells in the tumor.

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