Understand the molecular mechanism of age-associated decline in antiviral CD8 T cell immunity

总结

Summary Immunosenescence increases morbidity and mortality after infection and reduces vaccine efficacy. Most deaths associated with infections by influenza virus, SARS-CoV, or SARS-CoV-2 occurred in people older than 65. Thus, understanding the mechanism of age-associated decline in antiviral immunity is critical to the development of strategies to protect the elderly from viral pathogens. Despite its critical role in protection against infections, T- cell immunity declines with age. During aging, the prevalence of naïve T cells decreases, whereas the frequency of terminally differentiated CD8 T cells increases. In addition, aging reduces the responsiveness of naïve T cells to antigen. However, the molecular mechanism underlying age-associated decline in antiviral T cell immunity remains poorly defined. Using a mouse model of murine hepatitis virus (MHV) infection, we found that aging increased mortality and decreased antiviral CD4 and CD8 T cell responses. Surprisingly, although aging increased terminally differentiated CD8 T cells at baseline, there was a profound reduction in terminally differentiated effector CD8 T cells and an elevated gene-signature of T-cell exhaustion in aged mice after MHV infection. In addition, we showed that age-associated decline in T-cell expansion was primarily caused by TCR- triggered apoptosis and necroptosis pathways and was rescued by rebalancing TCR and IL2 signaling. We also found that aging reduced the metabolic rate of T cells at baseline and impaired metabolic adaptation of T cells after activation. Here, we hypothesize that age-associated exhaustion-prone epigenetic state and defective metabolic adaptation impair effector CD8 T cell response in viral infection. In this study, we will define the epigenetic and metabolic pathways in antiviral CD8 T cells altered by aging before and after infection, while accounting for age-associated changes in differentiation. We will also evaluate strategies that harness IL2 and TCR pathways to rescue age-related defects in antiviral CD8 T cells.