Age-dependent defects in the draining lymph node and naïve CD4+ T cell trafficking impair adaptive immunity and control of virus infection (VIR1P.1137)

Abstract

Abstract Although adaptive B and T cell responses decline with age, the basis for impaired immunity of the elderly against viruses remains uncertain. Herein, in the context of infection with West Nile virus (WNV), we identify new mechanisms for compromised adaptive immunity that occurs with aging. Old mice had blunted humoral immune responses to WNV, increased viral burden, and enhanced mortality. This decline in immunity and enhanced vulnerability to infection was associated with decreased trafficking capacity of naïve CD4+ T cells but not B cells from old mice, which manifested as impaired T cell diapedesis at high endothelial venules and reduced cell motility within draining lymph nodes (DLN) as judged by intravital microscopy, as well as delayed germinal center formation. Additionally, immune cell accumulation in the DLN after virus infection or antigen-adjuvant administration was diminished more generally in old mice and associated with a separate aging-related defect in local cytokine and chemokine production. Our results support a model in which age-dependent cell-intrinsic and cell-extrinsic defects result in delayed immune cell recruitment and antigen recognition in the DLN, which compromises induction of adaptive immune responses and contributes to the susceptibility of old animals to acute viral infections, and likely impaired vaccine responses.