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

🎉 Excited to share that our latest study has been published in eBioMedicine!
Our paper, "Differentiation-induced reduction in functional diversity restricts the ability of cytomegalovirus-specific CD8 T cells to eliminate virus-infected cells", sheds light on a critical paradox in human immunity: why individuals with large populations of Cytomegalovirus (HCMV)-specific T cells - often seen as a sign of strong immunity - may actually be more vulnerable to viral reactivation and long-term health complications.
🔍 Why it matters:
HCMV establishes lifelong latency, driving massive expansion of virus-specific CD8 T cells. While this seems protective, many people with high frequencies of these cells experience weakened immune control, linked to increased risks of coronary disease, frailty, and mortality.
💡 Our discovery:
By comparing HCMV-specific T cells in donors with low versus high frequencies, we found that T cells from donors with high frequencies are highly cytotoxic against HLA-expressing targets. However, these cells fail to kill infected cells with downregulated HLA molecule expression, a common immune evasion tactic of HCMV. In contrast, T cells from donors with low frequencies were still effective at eliminating HCMV-infected cells and produced higher levels of key cytokines, such as IFNγ and TNF.
🧠 The big picture:
HCMV appears to exploit T cell differentiation to reduce functional diversity, thus limiting the immune system’s ability to provide immune protection.
We believe these findings also open new avenues for understanding immune aging, improving adoptive T-cell therapy, and using HCMV as a vaccine vector.
📖 Read the full paper here: https://doi.org/10.1016/j.ebiom.2025.106107
🙏 Huge thanks to my incredible lab members, especially Lea Fritz, who led the project, collaborators, and the entire research team, for their dedication and hard work.