Aging Compromises Terminal Differentiation Program of Cytotoxic Effector Lineage and Promotes Exhaustion in CD8+ T Cells Responding to Coronavirus Infection

• DOI: 10.1111/acel.70109
• Publication Date: 2025-05-21T09:03:55Z
• Authors: Ziang Zhu; Guohua Lou; Ying Luo; Kiddist Yihunie; Jonathan Hoar; Juan A. Daniel; Bret M. Evers; Chen Yao; Tuoqi Wu
• Keywords: Coronavirus

ABSTRACT T cell aging increases the risk of viral infection‐related morbidity and mortality reduces vaccine efficacy in elderly. A major hallmark is loss quiescence shift toward terminal differentiation during homeostasis. However, how impacts program virus‐specific cells infection unclear. Here, a murine coronavirus (MHV) model with age‐associated increased mortality, we demonstrate that impairs, instead promoting, CD8 + cells. Upon infection, CD4 old mice showed marked reduction clonal expansion upregulation immune checkpoints associated exhaustion. Bulk single‐cell transcriptomics upregulated exhaustion transcriptional TOX shifted myeloid compartment from immunostimulatory to immunosuppressive phenotype. In addition, downregulated terminally differentiated effector diminished CX3CR1 cytotoxic lineage. Mechanistically, infected aged displayed defects inducing transcription factors ZEB2 KLF2, which were required for Together, our study shows impairs promotes responding through dysregulating expression lineage‐defining factors.