Inhibitory IL-10-producing CD4+ T cells are T-bet-dependent and facilitate cytomegalovirus persistence via coexpression of arginase-1

Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, Ladell, Kristin ORCID: https://orcid.org/0000-0002-9856-2938, Miners, Kelly L, Marsden, Morgan, Chapman, Lucy, Cardus Figueras, Anna, Scott, Jake, Andrews, Robert, Clare, Simon, Kriukova, Valeriia V, Lupyr, Ksenia R, Britanova, Olga V, Withers, David R, Jones, Simon A ORCID: https://orcid.org/0000-0001-7297-9711, Chudakov, Dmitriy M, Price, David A ORCID: https://orcid.org/0000-0001-9416-2737 and Humphreys, Ian R ORCID: https://orcid.org/0000-0002-9512-5337 2023. Inhibitory IL-10-producing CD4+ T cells are T-bet-dependent and facilitate cytomegalovirus persistence via coexpression of arginase-1. eLife 12 , e79165. 10.7554/eLife.79165

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Abstract

Inhibitory CD4+ T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity. However, the mechanisms that underpin the development of these regulatory cells, especially in the context of ongoing antigen exposure, have remained obscure. To address this knowledge gap, we undertook a comprehensive functional, phenotypic, and transcriptomic analysis of interleukin (IL)-10-producing CD4+ T cells induced by chronic infection with murine cytomegalovirus (MCMV). We identified these cells as clonally expanded and highly differentiated TH1-like cells that developed in a T-bet-dependent manner and coexpressed arginase-1 (Arg1), which promotes the catalytic breakdown of L-arginine. Mice lacking Arg1-expressing CD4+ T cells exhibited more robust antiviral immunity and were better able to control MCMV. Conditional deletion of T-bet in the CD4+ lineage suppressed the development of these inhibitory cells and also enhanced immune control of MCMV. Collectively, these data elucidated the ontogeny of IL-10-producing CD4+ T cells and revealed a previously unappreciated mechanism of immune regulation, whereby viral persistence was facilitated by the site-specific delivery of Arg1.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Medicine
Publisher:	eLife Sciences Publications
ISSN:	2050-084X
Funders:	Wellcome Trust
Date of First Compliant Deposit:	17 July 2023
Date of Acceptance:	11 May 2023
Last Modified:	22 Jul 2024 16:05
URI:	https://orca.cardiff.ac.uk/id/eprint/161027

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