CD8⁺ T cells not only are critical mediators of adaptive immunity but also may exhibit innate-like properties such as surface expression of NKG2C, an activating receptor typically associated with natural killer (NK) cells. We demonstrate that, similar to NK cells, NKG2C⁺TCRαβ⁺CD8⁺ T cells are associated with prior human cytomegalovirus (HCMV) exposure. In addition to expressing several NK cell markers such as CD56 and KIR, NKG2C⁺CD8⁺ T cells are oligoclonal and do not up-regulate PD-1 even in response to persistent activation. Furthermore, we found that NKG2C⁺CD8⁺ T cells from some individuals exhibited strong effector function against leukemia cells and HCMV-infected fibroblasts, which was dictated by both NKG2C and TCR specificity. Transcriptomic analysis revealed that the transcription factor BCL11B, a regulator of T cell developmental fate, is down-regulated in NKG2C⁺CD8⁺ T cells when compared with conventional NKG2C⁻CD8⁺ T cells. BCL11B deletion in conventional CD8⁺ T cells resulted in the emergence of a similar innate-like CD56⁺CD94⁺DAP12⁺NKG2C⁺CD45RA⁺CCR7⁻PD-1^−/low T cell population with activity against HLA-E⁺ targets. On the basis of their intrinsic capacity to recognize diseased cells coupled with lack of PD-1 induction, NKG2C⁺CD8⁺ T cells represent a lymphocyte population that resides at the boundary between innate and adaptive immunity, presenting an attractive alternative for cellular therapy, including CAR T cell–based therapies.

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