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IL-2 Regulates CD103 Expression on CD4⁺ T Cells in Scurfy Mice That Display Both CD103-Dependent and Independent Inflammation¹

Rahul Sharma^*, Sun-sang Joe Sung^*, Christian E. Abaya^*, Angela Chiao-Ying Ju^*, Shu Man Fu^*,,2 and Shyr-Te Ju^*,,3,2

*Center for Immunity, Inflammation, and Regenerative Medicine, Department of Medicine, and Department of Microbiology, University of Virginia, Charlottesville, VA 22908

Scurfy (Sf) mice lack CD4⁺Foxp3⁺ regulatory T cells and develop fatal multiorgan inflammation (MOI) mediated by CD4⁺ T cells. Introducing Il2^–/– gene into Sf mice (Sf.Il2^–/–) inhibited inflammation in skin and lung. As a major integrin receptor for the organs, we compared CD103 expression on the CD4⁺ T cells of B6, Il2^–/–, Sf, and Sf.Il2^–/– mice. CD103⁺CD4⁺ T cells, but not CD8⁺ T cells or CD11c⁺ dendritic cells, were significantly up-regulated only in Sf mice, indicating Il2^–/– dominantly and specifically inhibited CD103 up-regulation in Sf CD4⁺ T cells. In addition, CD4⁺Foxp3⁺ regulatory T cell CD103 expression was not reduced in Il2^–/– mice. Introducing CD103^–/– into Sf mice inhibited inflammation in skin and lung as compared with age-matched Sf mice, but they died at 7 wk old with inflammation developed in skin, lungs, and colon, demonstrating fatal MOI induced by CD103-independent mechanism. Transfer of Sf CD4⁺ T cells induced MOI more rapidly than CD103^–CD4⁺ T cells, indicating the presence of CD103-dependent mechanism for inflammation. In vitro stimulation with anti-CD3 plus anti-CD28 beads confirmed that CD103 induction in the CD4⁺Foxp3^– T cells in Il2^–/– and Sf.Il2^–/– is defective and cannot be restored by rIL-2 or rIL-15. The data indicate that IL-2 is required for optimal CD103 induction on CD4⁺ T cells in Sf mice and this effect contributes to inflammation in an organ-specific manner. IL-2 also has additional roles because the protection of skin and lung inflammation in Sf.Il2^–/–, but not Sf.CD103^–/– mice is lifelong and Sf.Il2^–/– mice have longer lifespan than Sf.CD103^–/– mice.

³ Address correspondence and reprint requests to Dr. Shyr-Te Ju, Room 5777, 5th Floor, Old Medical School Building, Hospital Drive, University of Virginia, Charlottesville, VA 22908-0412. E-mail address: sj8r{at}virginia.edu

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 AI-079906 (to S.-s.J.S.), and a grand-in-aid from the Beirne B. Carter Center of Immunology (to R.S.).

² S.M.F. and S.-T.J., co-senior authors, contributed equally to this study.

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