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A Novel Role of IL-2 in Organ-Specific Autoimmune Inflammation beyond Regulatory T Cell Checkpoint: Both IL-2 Knockout and Fas Mutation Prolong Lifespan of Scurfy Mice but by Different Mechanisms¹

Lingjie Zheng^2,*,, Rahul Sharma^2,, Felicia Gaskin, Shu Man Fu^2,*, and Shyr-Te Ju^2,3,*,

^* Department of Microbiology and Center of Immunity, Inflammation and Regenerative Medicine, Department of Medicine, and Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA 22908

Mutation of the Foxp3 transcription factor in Scurfy (Sf) mice results in complete absence of the CD4⁺Foxp3⁺ regulatory T cells (Tregs), severe multiorgan autoimmune syndrome, and early death at 4 wk of age. However, Sf mice simultaneously bearing the Il2^–/– (Sf.Il2^–/–) or Fas^lpr/lpr gene (Sf.Fas^lpr/lpr) have extended lifespan despite totally lacking Tregs, indicating a role of IL-2 and CD95 (Fas) signaling pathways in the multiorgan autoimmune syndrome beyond the Treg checkpoint. IL-2 has been implicated in regulating lymphoproliferation and CD178 (FasL) expression. However, Sf.Il2^–/– mice have increased lymphoproliferation and FasL expression. Importantly, the pattern of organ-specific autoimmune response of Sf.Il2^–/–mice resembled IL-2 knockout mice whereas that of Sf.Fas^lpr/lpr was similar to Sf mice, indicating that the distinct and weakened autoimmune manifestation in IL-2 knockout mice was not caused by the residual Tregs. Our study demonstrated a novel role of IL-2 in regulating multiorgan autoimmune inflammation beyond the Treg checkpoint and indicated that both Il2^–/– and Fas^lpr/lpr genes prolong the lifespan of Sf mice but by different mechanisms.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants DE-017579 and AR-051203 (to S.-T.J.), AR-047988 and AR-049449 (to S.M.F.), and a grant-in-aid from the Beirne B. Carter Center of Immunology (to R.S.).

² L.Z., R.S., S.-T.J., and S.M.F. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Shyr-Te Ju, Center of Immunity, Inflammation and Regenerative Medicine, University of Virginia, P.O. Box 800412, Old Medical School Building, Room 5777, Charlottesville, VA 22908. E-mail address: sj8r{at}virginia.edu

⁴ Abbreviations used in this paper: Treg, regulatory T cell; Sf, Scurfy; KO, knockout.

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The JI 2007 179: 7991-7992. [Full Text]