Dendritic cell NLRC4 regulates influenza A virus–specific CD4+ T cell responses through FasL expression
Emma E. Hornick, … , Fayyaz S. Sutterwala, Suzanne L. Cassel
Emma E. Hornick, … , Fayyaz S. Sutterwala, Suzanne L. Cassel
Published July 1, 2019; First published April 30, 2019
Citation Information: J Clin Invest. 2019;129(7):2888-2897. https://doi.org/10.1172/JCI124937.
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Research Article Immunology Virology

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.

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

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Figure 3

Increased death of IAV-specific CD4+ T cells in the lungs of Nlrc4–/– mice 7 days after infection.

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Increased death of IAV-specific CD4+ T cells in the lungs of Nlrc4–/– mi...
(A–C) Mice were infected with a 0.5 LD50 inoculum of IAV, and cells staining positive for the indicated markers and dyes were enumerated in the lungs on day 7 after infection by flow cytometry. (D) CD90.2+ WT and Nlrc4–/– hosts received 1 × 105 naive CD90.1/2+ WT and 1 × 105 CD90.1+ Nlrc4–/– OT-II cells i.v., followed 1 day later by infection with a 0.5 LD50 inoculum of IAV expressing OVA323–339. Seven days after infection, the indicated cells were quantified in the lungs. Data are representative of 2 independent experiments (n = 5–6 per group). Error bars represent the SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-tailed Student’s t test.