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X-linked Foxp3 (Scurfy) Mutation Dominantly Inhibits Submandibular Gland Development and Inflammation Respectively through Adaptive and Innate Immune Mechanisms¹

Rahul Sharma^*, Umesh S. Deshmukh^*, Lingjie Zheng, Shu Man Fu^2,*, and Shyr-Te Ju^2,3,*,

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

Scurfy (Foxp3^Sf/Y), Il2^–/–, and Il2r^–/– mice are deficient in CD4⁺Foxp3⁺ regulatory T cells (Treg), but only the latter two develop inflammation in the submandibular gland (SMG), a critical target of Sjögren’s syndrome. In this study, we investigated the reason that SMG of Scurfy (Sf), Sf.Il2^–/–, Sf.Il2r^–/–, and the long-lived Sf.Fas^lpr/lpr mice remained free of inflammation, even though their lymph node cells induced SMG inflammation in Rag1^–/– recipients. A strong correlation was observed between the development of the granular convoluted tubules (GCT) of the SMG in these mice and SMG resistance to inflammation. Moreover, GCT development in Sf.Rag1^–/– mice was not impeded, indicating a role of adaptive immunity. In the Sf.Fas^lpr/lpr mice, this block was linked to atrophy and inflammation in the accessory reproductive organs. Testosterone treatment restored GCT expression, but did not induce SMG inflammation, indicating GCT is not required for inflammation and additional mechanisms were controlling SMG inflammation. Conversely, oral application of LPS induced SMG inflammation, but not GCT expression. LPS treatment induced up-regulation of several chemokines in SMG with little effect on the chemokine receptors on CD4⁺ T cells in Sf mice. Our study demonstrates that Sf mutation affects SMG development through adaptive immunity against accessory reproductive organs, and the manifestation of SMG inflammation in Sf mice is critically controlled through innate immunity.

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 in part by National Institutes of Health Grants AR-051203 (to S.-T.J.), DE-017579 (to S.-T.J.), AR-045222 (to S.M.F.), AR-047988 (to S.M.F.), AR-049449 (to S.M.F.), and AR051391 (to U.S.D.), and a grant from Sjogren’s Syndrome Foundation (to U.S.D.).

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

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.

⁴ Abbreviations used in this paper: Treg, regulatory T cell; GCT, granular convoluted tubule; Sf, Scurfy; SMG, submandibular gland.