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
View: Text | PDF
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

×

Figure 1

IFN-λ signaling restricts virus replication in a murine model of SARS-CoV-2 infection.

Options: View larger image (or click on image) Download as PowerPoint
IFN-λ signaling restricts virus replication in a murine model of SARS-Co...
(A) WT and Ifnlr1–/– mice were infected intranasally with 1 × 105 TCID50 of SARS-CoV-2 MA10, and weight loss was monitored for 6 days. A 2-way ANOVA with Šidák’s multiple-comparison test determined significance. Data from 2 independent experiments pooled with data representing mean ± SEM. n = 10 mice/group. (B) At days 1, 2, 3, and 5 p.i., RNA was isolated from lungs of naive or infected mice. RNA was subjected to qPCR to determine N1 copies per μl. Data from 2 independent experiments pooled with data representing mean ± SEM. n = 6-8 mice/group. (C) Lungs were harvested from naive and infected mice at days 1, 2, 3, and 5 p.i., and virus was quantified by TCID50. Data from 2 independent experiments pooled with data representing mean ± SEM. n = 6–8 mice/group. Statistical significance in B and C was determined by 1-way ANOVA with Tukey’s multiple-comparison test. (D) ImageJ was utilized to quantify the average pixel intensity of 10 randomly selected 10× images from each lung. Significance was determined by 1-way ANOVA with Tukey’s multiple-comparison test, n = 3 mice/group with data representing mean ± SD. (E) IHC was performed to detect the SARS-CoV-2 nucleocapsid (N). Scale bar: 5 mm. (F) Representative images of SARS-CoV-2 N staining from individual animals on day 2 p.i. Scale bar: 1 mm.