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 2

IFN-λ signaling regulates pulmonary transcriptional programming during SARS-CoV-2 MA10 infection.

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IFN-λ signaling regulates pulmonary transcriptional programming during S...
RNA-Seq was performed on whole lungs of WT and Ifnlr1–/– naive mice or on days 2 and 5 following SARS-CoV-2 infection. (A) Quantification of differentially expressed genes (DEG) across WT or Ifnlr1–/– on days 2 and 5 following infection. Bar graphs represent total number of genes upregulated (red) or downregulated (blue) at the indicated time points. (B) Hierarchical clustering of the union of significantly up- or downregulated genes in WT or Ifnlr1–/– on days 2 and 5 following infection relative to naive. Heatmap represents the log2 fold change expression of 1277 DEG. Biweight midcorrelation was used to cluster transcripts in coexpression modules indicated by colors. (C) Enrichment of IPA canonical pathways from gene signatures derived from WT or Ifnlr1–/– mice during SARS-CoV-2 MA10 infection. Bubble plot represents the top 10 significantly enriched canonical pathways across day 2 and day 5 p.i. Bubble size indicates the -log10 P value of enrichment. Color indicates the inferred pathway activation Z score. Color indicates directionality of activation (purple) or repression (blue). White bubbles indicate significant pathways with no inferred activation state. (D and E) 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. (D) Relative expression of Ifit1, Ifit2, and Isg15 compared with the housekeeping gene Chmp2a was determined by qPCR. (E) Relative expression of Ifnl3, Ifnb1, and Ifna12 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.