Human cytomegalovirus expands a T cell population with loss of BCL11B expression and gain of NK cell identity

CD8+ T cells, critical mediators of adaptive immunity, may also 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+TCRaß+CD8+ T cells are associated with prior HCMV exposure. In addition to expressing several NK cell markers (CD56, KIR), NKG2C+CD8+ T cells are oligoclonal and do not upregulate PD1 despite chronic activation. Furthermore, NKG2C+CD8+ T cells from some individuals exhibit high effector function against leukemia cells and HCMV-infected fibroblasts, dictated by NKG2C and TCR specificity. Importantly, we observe that co-triggering of CD3 and NKG2C results in increased degranulation and IFN-? production by NKG2C+CD8+ T cells in an additive fashion. Transcriptomic analysis reveals that the transcription factor BCL11B, a regulator of T cell developmental fate, is significantly down-modulated in NKG2C+CD8+ T cells when compared to conventional NKG2C-CD8+ T cells. BCL11B deletion in conventional CD8 T cells results in the emergence of a CD56+CD94+DAP12+NKG2C+CD45RA+CCR7-PD1-/low T cell population with activity against HLA-E+ targets. Given their intrinsic capacity to recognize diseased cells coupled with lack of PD-1 upregulation despite chronic stimulation, NKG2C+CD8+ T cells represent a novel lymphocyte population that straddles the boundary between innate and adaptive immunity, presenting an attractive alternative for cellular therapy, including CAR T-based therapies. Overall design: RNA-seq was performed on CD8 T cells and NK cells harvested from PBMCs.