Dendritic cell NLRC4 regulates influenza A virus-specific CD4+ T cell responses through FasL expression

Abstract

Influenza A virus-specific (IAV-specific) T cell responses are important correlates of protection during primary and subsequent infections. The generation and maintenance of robust IAV-specific T cell responses relies on T cell interactions with dendritic cells (DCs). In this study, we explore the role of the nucleotide-binding domain leucine-rich repeat-containing receptor family member NLRC4 in modulating the DC phenotype during IAV infection. Nlrc4-/- mice had worsened survival and increased viral titers during infection, normal innate immune cell recruitment, and IAV-specific CD8+ T cell responses, but severely blunted IAV-specific CD4+ T cell responses compared with WT mice. The defect in the pulmonary IAV-specific CD4+ T cell response was not a result of defective priming or migration of these cells in Nlrc4-/-mice but was instead due to an increase in FasL+ DCs, resulting in IAV-specific CD4+ T cell death. Together, our data support a role for NLRC4 in regulating the phenotype of lung DCs during a respiratory viral infection and thereby influencing the magnitude of protective T cell responses.