IL-21 Restricts Virus-driven Treg Cell Expansion in Chronic LCMV Infection

PLoS Pathogens

Daniel Christ¹  Annette Oxenius²  Stefan Freigang³  Helge Frebel³  Tim Sparwasser⁴  Christoph Schneider⁵  Anja Fröhlich⁵  Manfred Kopf⁵  Iwana Schmitz⁵  Warren J. Leonard⁶ 

[1] Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia;Institute of Infection Immunology, TWINCORE/Centre for Experimental and Clinical Infection Research, Hannover, Germany;Institute of Microbiology, Department of Biology, ETH Zurich, Zurich, Switzerland;Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America;Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland;The University of New South Wales, Faculty of Medicine, St Vincent's Clinical School, Darlinghurst, Sydney, Australia

关键词: Regulatory T cells;    T cells;    Cytotoxic T cells;    Viral persistence;    latency;    Viral transmission;    infection;    Mouse models;    Immune response;    Spleen;   

DOI  :  10.1371/journal.ppat.1003362

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Foxp3+ regulatory T (Treg) cells are essential for the maintenance of immune homeostasis and tolerance. During viral infections, Treg cells can limit the immunopathology resulting from excessive inflammation, yet potentially inhibit effective antiviral T cell responses and promote virus persistence. We report here that the fast-replicating LCMV strain Docile triggers a massive expansion of the Treg population that directly correlates with the size of the virus inoculum and its tendency to establish a chronic, persistent infection. This Treg cell proliferation was greatly enhanced in IL-21R−/− mice and depletion of Treg cells partially rescued defective CD8+ T cell cytokine responses and improved viral clearance in some but not all organs. Notably, IL-21 inhibited Treg cell expansion in a cell intrinsic manner. Moreover, experimental augmentation of Treg cells driven by injection of IL-2/anti-IL-2 immune complexes drastically impaired the functionality of the antiviral T cell response and impeded virus clearance. As a consequence, mice became highly susceptible to chronic infection following exposure to low virus doses. These findings reveal virus-driven Treg cell proliferation as potential evasion strategy that facilitates T cell exhaustion and virus persistence. Furthermore, they suggest that besides its primary function as a direct survival signal for antiviral CD8+ T cells during chronic infections, IL-21 may also indirectly promote CD8+ T cell poly-functionality by restricting the suppressive activity of infection-induced Treg cells.

【 授权许可】

CC BY