title: Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus.
abstract: The origins and consequences of a regulatory T cell (Treg) disorder in systemic lupus erythematosus (SLE) are poorly understood. In the (NZBxNZW) F(1) mouse model of lupus, we found that CD4(+)Foxp3(+) Treg failed to maintain a competitive pool size in the peripheral lymphoid organs resulting in a progressive homeostatic imbalance of CD4(+)Foxp3(+) Treg and CD4(+)Foxp3(-) conventional T cells (Tcon). In addition, Treg acquired phenotypic changes that are reminiscent of IL-2 deficiency concomitantly to a progressive decline in IL-2-producing Tcon and an increase in activated, IFN-gamma-producing effector Tcon. Nonetheless, Treg from lupus-prone mice were functionally intact and capable to influence the course of disease. Systemic reduction of IL-2 levels early in disease promoted Tcon hyperactivity, induced the imbalance of Treg and effector Tcon, and strongly accelerated disease progression. In contrast, administration of IL-2 partially restored the balance of Treg and effector Tcon by promoting the homeostatic proliferation of endogenous Treg and impeded the progression of established disease. Thus, an acquired and self-amplifying disruption of the Treg-IL-2 axis contributed essentially to Tcon hyperactivity and the development of murine lupus. The reversibility of this homeostatic Treg disorder provides promising approaches for the treatment of SLE.
authors.affiliation: Department of Rheumatology and Clinical Immunology, University Hospital Charité, 10117 Berlin, Germany. humrich@drfz.de
authors.forename: Jens Y
authors.initials: JY
authors.lastname: Humrich
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.forename: Reinmar
authors.initials: R
authors.lastname: Undeutsch
authors.forename: Philipp
authors.initials: P
authors.lastname: Enghard
authors.forename: Stefan
authors.initials: S
authors.lastname: Rosenberger
authors.forename: Olivia
authors.initials: O
authors.lastname: Weigert
authors.forename: Lutz
authors.initials: L
authors.lastname: Kloke
authors.forename: Juliane
authors.initials: J
authors.lastname: Heimann
authors.forename: Timo
authors.initials: T
authors.lastname: Gaber
authors.forename: Susan
authors.initials: S
authors.lastname: Brandenburg
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheffold
authors.forename: Jochen
authors.initials: J
authors.lastname: Huehn
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
mesh_terms: D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006706:Homeostasis; D007376:Interleukin-2 / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D007376:Interleukin-2