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

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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.

Authors

Emma E. Hornick, Jargalsaikhan Dagvadorj, Zeb R. Zacharias, Ann M. Miller, Ryan A. Langlois, Peter Chen, Kevin L. Legge, Gail A. Bishop, Fayyaz S. Sutterwala, Suzanne L. Cassel