EBioMedicine · 2026
Differentiation-induced reduction in functional diversity restricts the ability of cytomegalovirus-specific CD8 T cells to eliminate virus-infected cells.
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Fritz Lea, Hassan Ahmed, Riemann Lennart, Čuvalo Berislav, Costa Bibiana, Wieland Britta, Eiz-Vesper Britta, Falk Christine, Roesner Lennart M, Werfel Thomas, Kalinke Ulrich, Georgiev Hristo, Förster Reinhold, Bošnjak Berislav
Аннотация
BACKGROUND: Human cytomegalovirus (HCMV) is one of the pathogens with the most significant impact on the immune system's composition, including the expansion of virus-specific CD8 T cells. Nevertheless, it remains unclear why individuals with expanded CD8 T cells recognising the pp65-HLA-A∗02:01-restricted viral epitope NLVPMVATV (NLV-T cells) exhibit weakened immune control of HCMV reactivation.
METHODS: Here, we characterised NLV-T cells from 116 healthy HCMV-positive donors, dividing them into two groups: those with low and those with high NLV-T cell frequencies (LF and HF, respectively). We phenotyped the cells using multi-colour spectral flow cytometry and single-cell RNA sequencing coupled with TCR profiling and examined their killing properties against peptide-loaded and virus-infected target cells.
FINDINGS: Our comprehensive multimodal analysis revealed that NLV-T cells from HF donors exhibited a phenotype of advanced differentiation, marked by high levels of granzyme B and perforin expression, and efficiently eliminated peptide-loaded targets and HCMV-infected cells as long as cell surface HLA expression was unaffected. However, NLV-T cells from LF donors, possessing a less differentiated granzyme K-intermediate phenotype, demonstrated enhanced cytokine secretion and the ability to eliminate HCMV-infected cells, even in the presence of virus-induced HLA class-I downregulation.
INTERPRETATION: Overall, these findings suggest that HCMV exploits CD8 T cell differentiation to evade immune protection. These data are crucial for understanding the previously observed decline in HCMV reactivation control in individuals with NLV-T cell accumulation. Moreover, our findings have clinical implications and could guide future research on adoptive T-cell therapy, and the potential use of HCMV as a vaccine vector.
FUNDING: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Projects number 390874280 and FO334/7-2.
METHODS: Here, we characterised NLV-T cells from 116 healthy HCMV-positive donors, dividing them into two groups: those with low and those with high NLV-T cell frequencies (LF and HF, respectively). We phenotyped the cells using multi-colour spectral flow cytometry and single-cell RNA sequencing coupled with TCR profiling and examined their killing properties against peptide-loaded and virus-infected target cells.
FINDINGS: Our comprehensive multimodal analysis revealed that NLV-T cells from HF donors exhibited a phenotype of advanced differentiation, marked by high levels of granzyme B and perforin expression, and efficiently eliminated peptide-loaded targets and HCMV-infected cells as long as cell surface HLA expression was unaffected. However, NLV-T cells from LF donors, possessing a less differentiated granzyme K-intermediate phenotype, demonstrated enhanced cytokine secretion and the ability to eliminate HCMV-infected cells, even in the presence of virus-induced HLA class-I downregulation.
INTERPRETATION: Overall, these findings suggest that HCMV exploits CD8 T cell differentiation to evade immune protection. These data are crucial for understanding the previously observed decline in HCMV reactivation control in individuals with NLV-T cell accumulation. Moreover, our findings have clinical implications and could guide future research on adoptive T-cell therapy, and the potential use of HCMV as a vaccine vector.
FUNDING: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)-Projects number 390874280 and FO334/7-2.