Parish, Ian AMarshall, Heather DStaron, Matthew MLang, Philipp ABrüstle, AnneChen, Jonathan HCui, WeiguoTsui, Yao-ChenPerry, CurtisLaidlaw, Brian JOhashi, PamelaWeaver, Casey TKaech, Susan M2016-01-182016-01-180021-9738http://hdl.handle.net/1885/95503During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.This work was supported by an Australian NHMRC Overseas Biomedical Postdoctoral Fellowship (to I.A. Parish); a Yale School of Medicine Brown-Coxe Postdoctoral Fellowship (to I.A. Parish); the Alexander von Humboldt Foundation (SKA2010, to P.A. Lang); a CIHR grant (to P.S. Ohashi); and by the Howard Hughes Medical Institute and NIH grant RO1AI074699 (to S.M. Kaech). P.S. Ohashi holds a Canada Research Chair in Autoimmunity and Tumor immunity.© 2014 American Society for Clinical Investigation. http://www.sherpa.ac.uk/romeo/issn/0021-9738..."author can archive publisher's version/PDF. Authors personal websites, institutional repositories and funding-body repositories" from SHERPA/RoMEO site (as at 18/01/16).animalschronic diseasecytokinesinflammation mediatorsinterleukin-10lymphocytic choriomeningitislymphocytic choriomeningitis virusmap kinase signaling systemmicemice, inbred c57blmice, knockoutmice, transgenicreceptors, antigen, t-cellt-lymphocyte subsetsth1 cellstranscription factors2014-07-0810.1172/JCI66108