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Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus
  1. J Humrich,
  2. R Undeutsch,
  3. L Kloke,
  4. G-R Burmester,
  5. G Riemekasten
  1. Department of Rheumatology and Clinical Immunology, University Hospital Charité, Germany

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The origins and consequences of a regulatory T cell (Treg) disorder in systemic lupus erythematosus (SLE) are poorly understood. In the (NZBxNZW) F1 mouse model of lupus, we found that CD4Foxp3+ Treg failed to maintain a competitive pool size in the peripheral lymphoid organs resulting in a progressive homeostatic imbalance of CD4Foxp3+ Treg and CD4Foxp3− conventional T cells (Tcon). In addition, Treg acquired phenotypic changes that are reminiscent of interleukin 2 (IL-2) deficiency concomitantly to a progressive decline in IL-2-producing Tcon and an increase in activated, IFNγ-producing effector Tcon. Nonetheless, Treg from lupusprone mice were functionally intact and capable to influence the course of disease as shown by adoptive transfer of Treg into mice with already established 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. IL-2 treatment of diseased mice also strongly impeded disease progression that was most efficient by application of a repetitive regimen. In summary, 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 novel and promising approaches for the selective treatment of SLE.

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