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.
journal_name
Proc Natl Acad Sci U S Aauthors
Humrich JY,Morbach H,Undeutsch R,Enghard P,Rosenberger S,Weigert O,Kloke L,Heimann J,Gaber T,Brandenburg S,Scheffold A,Huehn J,Radbruch A,Burmester GR,Riemekasten Gdoi
10.1073/pnas.0903158107subject
Has Abstractpub_date
2010-01-05 00:00:00pages
204-9issue
1eissn
0027-8424issn
1091-6490pii
0903158107journal_volume
107pub_type
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