Differentiation-induced reduction in functional diversity restricts the ability of cytomegalovirus-specific CD8 T cells to eliminate virus-infected cells

Individuals with expanded CD8 T cells recognizing the pp65-HLA-A*02:01–restricted viral epitope NLVPMVATV (NLV-T cells) have weakened immune control of human cytomegalovirus (HCMV) reactivation. Here, we characterized NLV-T cells from healthy HCMV-positive donors, dividing them into two groups: those with low and those with high NLV-T cell frequencies (LF and HF, respectively). Our comprehensive multimodal analysis revealed that NLV-T cells from HF donors preferentially exhibit a phenotype of advanced differentiation, characterized by granzyme B and perforin expression. Although these cells were more efficient in eliminating peptide-loaded target cells than NLV-T cells from LF donors, the latter were more potent in cytokine secretion and the elimination of HCMV-infected cells with virus-induced HLA class-I downregulation. Overall, these findings suggest that HCMV exploits CD8 T cell differentiation to evade immune protection and explain the previously observed decline in HCMV reactivation control in individuals with NLV-T cell accumulation.