IFN-λ uniquely promotes CD8 T cell immunity against SARS-CoV-2 relative to type I IFN
Abigail D. Solstad, Parker J. Denz, Adam D. Kenney, Najmus S. Mahfooz, Samuel Speaks, Qiaoke Gong, Richard T. Robinson, Matthew E. Long, Adriana Forero, Jacob S. Yount, Emily A. Hemann
Abigail D. Solstad, Parker J. Denz, Adam D. Kenney, Najmus S. Mahfooz, Samuel Speaks, Qiaoke Gong, Richard T. Robinson, Matthew E. Long, Adriana Forero, Jacob S. Yount, Emily A. Hemann
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Research Article Immunology Infectious disease

IFN-λ uniquely promotes CD8 T cell immunity against SARS-CoV-2 relative to type I IFN

Abstract

Optimization of protective immune responses against SARS-CoV-2 remains an urgent worldwide priority. In this regard, type III IFN (IFN-λ) restricts SARS-CoV-2 infection in vitro, and treatment with IFN-λ limits infection, inflammation, and pathogenesis in murine models. Furthermore, IFN-λ has been developed for clinical use to limit COVID-19 severity. However, whether endogenous IFN-λ signaling has an effect on SARS-CoV-2 antiviral immunity and long-term immune protection in vivo is unknown. In this study, we identified a requirement for IFN-λ signaling in promoting viral clearance and protective immune programming in SARS-CoV-2 infection of mice. Expression of both IFN and IFN-stimulated gene (ISG) in the lungs were minimally affected by the absence of IFN-λ signaling and correlated with transient increases in viral titers. We found that IFN-λ supported the generation of protective CD8 T cell responses against SARS-CoV-2 by facilitating accumulation of CD103+ DC in lung draining lymph nodes (dLN). IFN-λ signaling specifically in DCs promoted the upregulation of costimulatory molecules and the proliferation of CD8 T cells. Intriguingly, antigen-specific CD8 T cell immunity to SARS-CoV-2 was independent of type I IFN signaling, revealing a nonredundant function of IFN-λ. Overall, these studies demonstrate a critical role for IFN-λ in protective innate and adaptive immunity upon infection with SARS-CoV-2 and suggest that IFN-λ serves as an immune adjuvant to support CD8 T cell immunity.

Authors

Abigail D. Solstad, Parker J. Denz, Adam D. Kenney, Najmus S. Mahfooz, Samuel Speaks, Qiaoke Gong, Richard T. Robinson, Matthew E. Long, Adriana Forero, Jacob S. Yount, Emily A. Hemann

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Figure 3

IFN-λ signaling regulates CD103+ DC populations in the lungs.

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IFN-λ signaling regulates CD103+ DC populations in the lungs. (A and B) ...
(A and B) WT and Ifnlr1–/– mice were infected intranasally with 1 × 105 TCID50 of SARS-CoV-2 MA10, and RNA was isolated from lungs of naive or infected mice on days 1, 2, 3, and 5 p.i. Relative expression of Il6 and Il10 (A), as well as Cxcl1 and Cxcl10 (B), compared with the housekeeping gene Chmp2a was determined by qPCR. Statistical significance was calculated by 1-way ANOVA followed by Tukey’s multiple-comparison test. Two independent experiments pooled with data representing mean ± SEM. n = 6–11 mice/group. (C and D) WT and Ifnlr1–/– mice were infected intranasally with 1 × 105 TCID50 of SARS-CoV-2 MA10. On day 4 p.i., lungs were harvested and numbers of specific immune cell (CD45+) populations were determined by flow cytometry. (C) Total numbers of alveolar macrophages, neutrophils, eosinophils, CD11c+CD11b+MHCII+ cells (iDC), pDCs, NK cells (NK1.1+), B cells, CD4 T cells, and CD8 T cells in the lungs was and N219-specific CD8 T cells were determined by flow cytometry. (D) Representative flow plots displaying the frequency and graphs quantifying numbers of WT and Ifnlr1–/– mice at day 4 following SARS-CoV-2 MA10 infection. Data from 2 independent experiments pooled with data representing mean ± SEM. n = 10–11 mice/group. Statistical significance was determined by unpaired 2-tailed t test. Frequencies on representative flow plots represent the percentage of parent gate (directly upstream of gate named in figure) with gating strategy shown in Supplemental Figure 2.