Human Granzyme K Is a Feature of Innate T Cells in Blood, Tissues, and Tumors, Responding to Cytokines Rather than TCR Stimulation

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⁺CD62L²Tcf7^int, 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-g 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-g, 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.