title: Inflammation and lymphopenia trigger autoimmunity by suppression of IL-2-controlled regulatory T cell and increase of IL-21-mediated effector T cell expansion.
abstract: The dynamic interplay between regulatory T cells (T(regs)) and effector T cells (T(effs)) governs the balance between tolerance and effector immune responses. Perturbations of T(reg) frequency and function or imbalances in T(reg)/T(eff) levels are associated with the development of autoimmunity. The factors that mediate these changes remain poorly understood and were investigated in this study in murine autoimmune arthritis. T(regs) displayed a stable phenotype in arthritic mice and were fully functional in in vitro suppression assays. However, their expansion was delayed relative to T(effs) (T follicular helper cells and Th17 cells) during the early stages of autoimmune reactivity. This imbalance is likely to have led to insufficient T(reg) control of T(effs) and induced autoimmunity. Moreover, a counterregulatory and probably IL-7-driven increase in thymic T(reg) production and recruitment to inflamed tissues was too slow for disease prevention. Increased T(eff) over T(reg) expansion was further aggravated by inflammation and lymphopenia. Both these conditions contribute to autoimmune pathogenesis and were accompanied by decreases in the availability of IL-2 and increases in levels of IL-21. IL-2 neutralization or supplementation was used to show that T(reg) expansion mainly depended on this cytokine. IL-21R(-/-) cells were used to demonstrate that IL-21 promoted the maintenance of T(effs). Thus, at inflammatory sites in experimental arthritis, a deficit in IL-2 hampers T(reg) proliferation, whereas exaggerated IL-21 levels overwhelm T(reg) control by supporting T(eff) expansion. This identifies IL-2 and IL-21 as targets for manipulation in therapies for autoimmunity.
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Medical Centre Freiburg, 79106 Freiburg, Germany; Center for Immunology and Inflammation, Monash University Clayton, Melbourne, Victoria 3088, Australia; Immunology Department, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia; nina.chevalier@uniklinik-freiburg.de charles.mackay@monash.edu.
authors.forename: Nina
authors.initials: N
authors.lastname: Chevalier
authors.affiliation: Center for Immunology and Inflammation, Monash University Clayton, Melbourne, Victoria 3088, Australia;
authors.forename: Alison N
authors.initials: AN
authors.lastname: Thorburn
authors.affiliation: Center for Immunology and Inflammation, Monash University Clayton, Melbourne, Victoria 3088, Australia;
authors.forename: Laurence
authors.initials: L
authors.lastname: Macia
authors.affiliation: Center for Immunology and Inflammation, Monash University Clayton, Melbourne, Victoria 3088, Australia;
authors.forename: Jian
authors.initials: J
authors.lastname: Tan
authors.affiliation: Center for Immunology and Inflammation, Monash University Clayton, Melbourne, Victoria 3088, Australia;
authors.forename: Laurent
authors.initials: L
authors.lastname: Juglair
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, 113-8421 Tokyo, Japan; and.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Center for Immunology and Inflammation, Monash University Clayton, Melbourne, Victoria 3088, Australia;
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.affiliation: Centre for Asthma and Respiratory Diseases, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales 2300, Australia.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hansbro
authors.affiliation: Center for Immunology and Inflammation, Monash University Clayton, Melbourne, Victoria 3088, Australia;
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
mesh_terms: D000818:Animals; D001168:Arthritis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015551:Autoimmunity; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D007108:Immune Tolerance; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008231:Lymphopenia / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D000098546:Interleukin-21
chemical_list: D007376:Interleukin-2; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21