Influenza A Virus Disruption of Dendritic Cell-Natural Killer Cell Crosstalk Impacts Activation of Helper and Cytotoxic T cell Subsets

Dendritic cells (DC) and Natural killer (NK) cells engage in reciprocal interactions to trigger an efficient innate immune response while governing the adaptive immune response. Here we used an ex vivo autologous human primary immune cell co-culture of DCs and NK cells to investigate the impact of DC-NK cell crosstalk on activation of CD4+ and CD8+ naive T cell responses to influenza A viral (IAV) infection. Using multiparameter flow cytometry, we observed that culturing T cells with DC and NK cells led to enhanced expression of CD69 and CD25 activation markers and increased proliferative ability of both CD4+ and CD8+ T cell subsets. Exposure of DCs to the pandemic A/California/07/2009 (H1N1) strain in NK cell co-culture led to a reduced frequency of CD4+CD69+, CD8+CD69+, CD4+CD25+, CD8+CD25+ T cell subsets and a reduced expansion of CD4+ T cells. The IAV-mediated curtailment of T cell activation was dependent on the ability of A/California/07/2009 (H1N1) to replicate as inactivation of the virus rescued expression of CD69, CD25 on both CD4+ and CD8+ T cell subsets and triggered expansion of CD4+ T cells. Further, we discovered exposure of DCs to the A/Victoria/361/2011 (H3N2) IAV strain also significantly impaired expression of CD69 on CD4+ and CD8+ T cells and CD25 on CD8+ T cells. In contrast with the A/California/07/2009 (H1N1 strain), inactivation of A/Victoria/361/2011 (H3N2) failed to fully restore T cell expression of CD69 and CD25 and proliferation. Collectively, these data demonstrate that IAV partially usurps the ability of DC-NK cell crosstalk to activate naive CD4+ and CD8+ T cells in a strain-dependent manner. These data may inform the immunological signals required to trigger a potent cellular immune response to IAV, which may elicit broader and more durable protection than current inactivated vaccine platforms.