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SOCS1 Regulates CCR7 Expression and Migration of CD4⁺ T Cells into Peripheral Tissues¹

Cheng-Rong Yu^*, Rashid M. Mahdi^*, Xuebin Liu^*, Allen Zhang^*, Tetsuji Naka, Tadamitsu Kishimoto and Charles E. Egwuagu^2,*

^* Laboratory of Immunology, Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; and Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Osaka, Japan

Suppressors of cytokine signaling (SOCS) proteins control many aspects of lymphocyte function through regulation of STAT pathways. SOCS1-deficient mice develop severe skin and eye diseases that result from massive infiltration of inflammatory cells into these tissues. In this study, we have used SOCS1-, STAT1-, or STAT6-deficient mice, as well as, T cells with stable overexpression or deletion of SOCS1, to examine whether SOCS1 is involved in regulating lymphocyte trafficking to peripheral tissues. We show that SOCS1-deficient mice have increased numbers of T cells with characteristics of effector memory cells and expression of CCR7, a protein that promotes retention of T cells in lymphoid tissues, is markedly reduced in these cells. The decrease in CCR7 expression correlates with hyperactivation of STAT6, suggesting that aberrant recruitment of T cells into SOCS1-deficient mouse skin or eye results from abrogation of negative feedback regulation of STAT6 activation and CCR7 expression. Consistent with in vivo regulation of CCR7 expression and lymphocyte migration by SOCS1, forced overexpression of SOCS1 in T cells up-regulates CCR7 expression and enhances chemotaxis toward CCL19 or CCL21. CCR6 and CXCR3 are also up-regulated on SOCS1-deficient T cells and in situ analysis of the cornea or retina further reveal that these cells may mediate the chronic skin and eye inflammation through recruitment of Th1 and Th17 cells into these tissues. Collectively, these results suggest that SOCS1 regulates steady-state levels of chemokine receptors through its inhibitory effects on STAT pathways and this may underscore its role in regulating recruitment and retention of effector cells into nonlymphoid tissues.

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 Intramural Research Programs of the National Eye Institute and the U.S. National Institutes of Health.

² Address correspondence and reprint requests to Dr. Charles E. Egwuagu, Laboratory of Immunology, Molecular Immunology Section, National Institutes of Health, Building 10, Room 10N116, 10 Center Drive, Bethesda, MD 20892. E-mail address: egwuaguc{at}nei.nih.gov

³ Abbreviations used in this paper: SOCS, suppressor of cytokine signaling; HEL, hen egg lysozyme; WT, wild type; DKO, double knockout; RPA, RNase protection assay; ELC, EBV-induced molecule 1 ligand chemokine; SLC, secondary lymphoid tissue chemokine.