Bona Fide Th17 Cells without Th1 Functional Plasticity Protect against Influenza

Author:

Dhume Kunal1,Finn Caroline M.1,Devarajan Priyadharshini2ORCID,Singh Ayushi1ORCID,Tejero Joanne D.1,Prokop Emily1ORCID,Strutt Tara M.1ORCID,Sell Stewart3ORCID,Swain Susan L.2ORCID,McKinstry Karl Kai1ORCID

Affiliation:

1. *Division of Immunity and Pathogenesis, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL;

2. †Department of Pathology, University of Massachusetts Medical School, Worcester, MA; and

3. ‡Palisades Pathology Laboratory, Williamsburg, VA

Abstract

Abstract Optimal transcriptional programming needed for CD4 T cells to protect against influenza A virus (IAV) is unclear. Most IAV-primed CD4 T cells fit Th1 criteria. However, cells deficient for the Th1 “master regulator,” T-bet, although marked by reduced Th1 identity, retain robust protective capacity. In this study, we show that T-bet’s paralog, Eomesodermin (Eomes), is largely redundant in the presence of T-bet but is essential for the residual Th1 attributes of T-bet–deficient cells. Cells lacking both T-bet and Eomes instead develop concurrent Th17 and Th2 responses driven by specific inflammatory signals in the infected lung. Furthermore, the transfer of T-bet– and Eomes-deficient Th17, but not Th2, effector cells protects mice from lethal IAV infection. Importantly, these polyfunctional Th17 effectors do not display functional plasticity in vivo promoting gain of Th1 attributes seen in wild-type Th17 cells, which has clouded evaluation of the protective nature of Th17 programming in many studies. Finally, we show that primary and heterosubtypic IAV challenge is efficiently cleared in T-bet– and Eomes double-deficient mice without enhanced morbidity despite a strongly Th17-biased inflammatory response. Our studies thus demonstrate unexpectedly potent antiviral capacity of unadulterated Th17 responses against IAV, with important implications for vaccine design.

Funder

HHS | NIH | National Institute of Allergy and Infectious Diseases

UCF | College of Medicine, University of Central Florida

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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