Age-Dependent Cell Trafficking Defects in Draining Lymph Nodes Impair Adaptive Immunity and Control of West Nile Virus Infection

Impaired immune responses in the elderly lead to reduced vaccine efficacy and increased susceptibility to viral infections. Although several groups have documented age-dependent defects in adaptive immune priming, the deficits that occur prior to antigen encounter remain largely unexplored. Herein, we identify novel mechanisms for compromised adaptive immunity that occurs with aging in the context of infection with West Nile virus (WNV), an encephalitic flavivirus that preferentially causes disease in the elderly. An impaired IgM and IgG response and enhanced vulnerability to WNV infection during aging was linked to delayed germinal center formation in the draining lymph node (DLN). Adoptive transfer studies and two-photon intravital microscopy revealed a decreased trafficking capacity of donor naïve CD4+ T cells from old mice, which manifested as impaired T cell diapedesis at high endothelial venules and reduced cell motility within DLN prior to antigen encounter. Furthermore, leukocyte accumulation in the DLN within the first few days of WNV infection or antigen-adjuvant administration was diminished more generally in old mice and associated with a second aging-related defect in local cytokine and chemokine production. Thus, age-dependent cell-intrinsic and environmental defects in the DLN result in delayed immune cell recruitment and antigen recognition. These deficits compromise priming of early adaptive immune responses and likely contribute to the susceptibility of old animals to acute WNV infection.
Author Summary While West Nile virus (WNV) infection preferentially causes severe neuroinvasive disease in elderly humans, the basis for this epidemiological linkage has remained uncertain. Here, we studied the impact of aging on WNV pathogenesis and immune responses using a mouse model of infection. Old mice showed increased lethality after WNV infection compared to adult mice, and this phenotype was associated with delayed antibody responses, and higher levels of virus infection in the blood, spleen, and brain. Detailed immunological and microscopic analyses revealed defects in germinal center development in the draining lymph node and impaired migratory capacity of naïve CD4+ T cells within days of WNV infection. This deficit was worsened by a separate age-related deficiency in the production of several chemokines that recruit leukocytes to inflamed lymph nodes. Thus, age-dependent defects in naïve CD4+ T cell trafficking and in the draining lymph node environment result in delayed initiation of antiviral responses and a failure to control WNV, which ultimately contributes to higher rates of mortality after infection.