Antigen presenting cell subsets in the lung and draining lymph nodes affect granzyme B-expressing CD4+ T cells in the lung during influenza A infection

Abstract

Abstract Influenza A virus (IAV) is a global health burden that evades vaccine responses and can present as a pandemic threat. Innate immune cells are the first line of defense at the mucosal site of entry and drive adaptive responses that provide immunity. Therefore, we examined the distinct antigen-presenting cell (APC) populations in the lung and draining lymph nodes that respond to IAV infection. When mice are treated intranasally with PR8, a highly inflammatory H1N1 IAV, the populations of APCs in the lung change, inducing infiltration of a large population of inflammatory macrophages and a concomitant decrease in dendritic cells. These inflammatory macrophages express increased levels of TLR9 after infection, corresponding with our previous work demonstrating the efficacy of CpG DNA in driving anti-IAV responses. These changes in APC subsets do not occur in a similar fashion after infection with X31, a low inflammation H3N2 virus, or in the lymph nodes. One significant response is the production of granzyme B (GzB) in CD4+ T cells that infiltrate the lung after IAV infection. APC populations were sorted after PR8 infection and used to stimulate DO11.10 T cells in vitro. CD11b+ APCs were most efficient at inducing GzB in CD4+ T cells in steady-state, while after infection both CD11b+ and CD11b+CD11c+ APCs induced strong GzB expression, while all APC subsets induced IL-2 and IFN-gamma release from CD4+ T cells. These results have implications for vaccine design and we are currently utilizing chimeric antibodies to target antigen to APC populations in the lung and lymph nodes to induce anti-IAV CD4+ T cell responses.