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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 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

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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

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Figure 1

Nlrc4–/– mice have reduced survival and viral clearance during IAV infection.

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Nlrc4–/– mice have reduced survival and viral clearance during IAV infe...
(A–E) Mice were infected with a 0.5 LD50 (A–C and E) or 0.25 LD50 (D) inoculum of IAV. Mortality (A and D) and weight loss (B) were monitored, and pulmonary viral titers (C) were quantified by plaque assay at the indicated time points after infection. (E) Caspase-1 cleavage was assessed in lungs 24 hours after infection with IAV. Each lane represents 1 mouse. (F–J) Innate immune cells in the lungs were quantified at the indicated time points after infection. In addition to the markers shown, dead cells and doublets were excluded, and then cells were gated on CD45.2 expression. Data are from 1 experiment (E, n = 3 per group and D, n = 8–10 per group), or were pooled from 2 (A and B, n = 14 per group, and C, n = 5–9 per group) or 3 (F–J, n = 12–14 per group) separate experiments. *P < 0.05, **P < 0.01, and ***P < 0.001, by Mantel-Cox test (A and D), 1-way ANOVA with Tukey’s post hoc analysis (B), and 2-tailed Student’s t test (C). Mo, monocytes; MΦ, macrophages.

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