RT Journal Article SR Electronic T1 Inhibitory IL-10-producing CD4+ T cells develop in a T-bet-dependent manner and facilitate cytomegalovirus persistence via coexpression of arginase-1 JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.01.25.477742 DO 10.1101/2022.01.25.477742 A1 Mathew Clement A1 Kristin Ladell A1 Kelly L. Miners A1 Morgan Marsden A1 Lucy Chapman A1 Anna Cardus Figueras A1 Jake Scott A1 Robert Andrews A1 Simon Clare A1 Valeriia V. Kriukova A1 Ksenia R. Lupyr A1 Olga V. Britanova A1 David R. Withers A1 Simon A. Jones A1 Dmitriy M. Chudakov A1 David A. Price A1 Ian R. Humphreys YR 2022 UL http://biorxiv.org/content/early/2022/01/27/2022.01.25.477742.abstract AB Inhibitory CD4+ T cells have been linked with suboptimal immune responses against cancer and pathogen chronicity, but the mechanisms that underpin the development of such regulatory networks in vivo have remained obscure. To address this knowledge gap, we performed a comprehensive functional, phenotypic, and transcriptomic analysis of 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 at sites of viral persistence 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 enabled better 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 coexpression of Arg1.Competing Interest StatementThe authors have declared no competing interest.