Publication date: May 21, 2025

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

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Original Article