IFN-λ uniquely promotes CD8 T cell immunity against SARS-CoV-2 relative to type I IFN
Abigail D. Solstad, … , Jacob S. Yount, Emily A. Hemann
Abigail D. Solstad, … , Jacob S. Yount, Emily A. Hemann
Published July 8, 2024
Citation Information: JCI Insight. 2024;9(13):e171830. https://doi.org/10.1172/jci.insight.171830.
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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 5

IFN-λ signaling in DC is necessary for CD103+ DC and N219+ CD8 T cell responses in dLN and CD8 T cell proliferation during SARS-CoV-2 MA10 infection.

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IFN-λ signaling in DC is necessary for CD103+ DC and N219+ CD8 T cell re...
WT and Ifnlr1–/– mice were administered 1 × 104 TCID50 of SARS-CoV-2 MA10 and, on day 4 p.i., dLN were harvested. (A and B) The number and frequency of CD103+ DCs (A) and N219-specific CD8 T cells (B) were assessed by flow cytometry. Data from 2 independent experiments pooled with data representing mean ± SEM. n = 8–11 mice/group. Statistical significance was determined by unpaired t test. Frequencies on representative flow plots represent the percentage of parent gate (directly upstream of gate named in figure). (C) BMDC generated from WT and Ifnlr1–/– mice were infected with SARS-CoV-2 and cocultured for 2.5 days with WT or Ifnlr1–/– CFSE-labeled CD8 T cells purified from spleens of mice. (D and E) After 2.5 days, CD86 expression on BMDC (D) and CD8 T cell proliferation as measured by CFSE dilution (E) was quantified by flow cytometry. Statistical significance was calculated by 1-way ANOVA followed by Tukey’s multiple-comparison test. Data from 2 individual experiments pooled with data representing mean ± SEM. n = 6–8 mice/group with each data point representing BMDC harvested from an individual mouse.