title: IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis.
abstract: Modulation of regulatory T cell (Treg) suppression has important implications for vaccine development, the effectiveness of tumor surveillance, and the emergence of autoimmunity. We have previously shown that the cytokine IL-21 can counteract Treg suppression. However, whether this reflects an effect of IL-21 on Treg, conventional T cells, or antigen-presenting cells is not known. Here we have used lymphocyte populations from IL-21R-deficient mice to pinpoint which cell type needs to be targeted by IL-21 for Treg suppression to be overcome. We show that IL-21 counteracts suppression by acting on conventional T cells and that this is associated with inhibition of IL-2 production. Despite the lack of IL-2, conventional T-cell responses proceed unimpaired because IL-21 can substitute for IL-2 as a T cell growth factor. However, IL-21 is unable to substitute for IL-2 in supporting the Treg compartment. Thus, IL-21 signaling in conventional T cells indirectly impacts Treg homeostasis by decreasing IL-2 availability. These data demonstrate that IL-21 and IL-2 can have overlapping roles in promoting conventional T-cell responses but play distinct roles in controlling Treg homeostasis and function. The data also suggest a new paradigm whereby cytokines can promote immunity by inhibiting IL-2.
authors.affiliation: Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham, UK.
authors.forename: Kesley
authors.initials: K
authors.lastname: Attridge
authors.forename: Chun Jing
authors.initials: CJ
authors.lastname: Wang
authors.forename: Lukasz
authors.initials: L
authors.lastname: Wardzinski
authors.forename: Rupert
authors.initials: R
authors.lastname: Kenefeck
authors.forename: Jayne L
authors.initials: JL
authors.lastname: Chamberlain
authors.forename: Claire
authors.initials: C
authors.lastname: Manzotti
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
authors.forename: Lucy S K
authors.initials: LS
authors.lastname: Walker
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism*; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000098546:Interleukin-21
chemical_list: C508118:Il21r protein, mouse; D007376:Interleukin-2; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D000098546:Interleukin-21