Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus.
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.
Humrich
Jens Y
JY
Department of Rheumatology and Clinical Immunology, University Hospital Charité, 10117 Berlin, Germany. humrich@drfz.de
Morbach
Henner
H
Undeutsch
Reinmar
R
Enghard
Philipp
P
Rosenberger
Stefan
S
Weigert
Olivia
O
Kloke
Lutz
L
Heimann
Juliane
J
Gaber
Timo
T
Brandenburg
Susan
S
Scheffold
Alexander
A
Huehn
Jochen
J
Radbruch
Andreas
A
Burmester
Gerd-Rüdiger
GR
Riemekasten
Gabriela
G
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*
D007376:Interleukin-2