Aging compromises effector differentiation and induces exhaustion-like phenotype in CD8 T cells 2511

Description Immunosenescence leads to impaired immunity against infections in the elderly. As a key component of adaptive immunity, T cells are crucial for immunity against infection and cancer and exhibit distinct phenotypic changes with age. Characterizing these age-related alterations in T cells is essential for developing strategies to address immune dysregulation in the elderly. In vitro activation model showed that aged mice have a higher frequency of PD1+ exhausted-like CD8 T cells at baseline and higher TCR-induced cell death upon activation. Inhibiting both apoptosis and necrosis rescues TCR activation-induced cell death. Using a murine hepatitis virus (MHV) intranasal infection model, we observed that aged mice had greater weight loss, higher mortality, and impaired CD8 T cell responses during MHV infection. Infected aged mice exhibited increased expression of inhibitory receptors on antiviral CD8 T cells and a decrease in the population of CD8 T cells producing IFN-γ. Single-cell RNA sequencing showed that aging altered the transcriptional profile of antiviral CD8 T cells and reduced T-Bet and ZEB2 expression, key factors for effector CD8 T cell differentiation. Aging also upregulated T cell exhaustion gene signature mediated by the transcription factor TOX. Overall, our findings demonstrate that aging reshapes the molecular program of antiviral CD8 T cells and compromised antiviral T cell immunity in the aged. Funding Sources Supported by NIH/ NIA AG-083398; NIAID AI-158294 Topic Categories Viral Immunology (VIR)