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

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.