title: IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection.
abstract: 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.
authors.affiliation: Molecular Biomedicine, Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Iwana
authors.initials: I
authors.lastname: Schmitz
authors.forename: Christoph
authors.initials: C
authors.lastname: Schneider
authors.forename: Anja
authors.initials: A
authors.lastname: Fröhlich
authors.forename: Helge
authors.initials: H
authors.lastname: Frebel
authors.forename: Daniel
authors.initials: D
authors.lastname: Christ
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Annette
authors.initials: A
authors.lastname: Oxenius
authors.forename: Stefan
authors.initials: S
authors.lastname: Freigang
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D049109:Cell Proliferation; D002908:Chronic Disease; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D000098546:Interleukin-21