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ICOS Controls Effector Function but Not Trafficking Receptor Expression of Kidney-Infiltrating Effector T Cells in Murine Lupus¹

Jared M. Odegard^2,*, Leah D. DiPlacido^2,*, Lark Greenwald^*, Michael Kashgarian, Dwight H. Kono^¶, Chen Dong^3,*, Richard A. Flavell^*, and Joe Craft^4,*,

^* Department of Immunobiology, Department of Pathology, Howard Hughes Medical Institute, and Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT 06520; and ^¶ Department of Immunology & Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037

Renal pathology in systemic lupus erythematosus involves both autoantibody deposition and a cellular inflammatory response, both of which are mediated by effector CD4 T cells. MRL^lpr mice spontaneously develop massive perivascular infiltrates, but the pathways that regulate the development, trafficking, and effector functions of kidney-infiltrating T cells are poorly defined. To address these questions, we first surveyed inflammatory chemokine protein levels in nephritic kidneys from lupus-prone MRL^lpr mice. After identifying highly elevated levels of the CXCR3 ligand CXCL9, we found that kidney-infiltrating effectors are enriched for expression of CXCR3, as well as P-selectin ligand and ICOS. Using genetic ablation, we demonstrate that ICOS plays an essential role in the establishment of renal perivascular infiltrates, although a small number of infiltrating cells remain around the blood vessels. Interestingly, though IgG autoantibody production is substantially reduced in Icos^–/– MRL^lpr mice, the progression of immune complex glomerulonephritis is only modestly diminished and the production of inflammatory chemokines, such as CXCL9, remains high in the kidney. We find that Icos^–/– effector cell numbers are only slightly reduced and these have normal expression of CXCR3 and P-selectin ligand with intact migration to CXCL9. However, they have impaired production of inflammatory cytokines and fail to show evidence of efficient proliferation in the kidney. Thus, while dispensable for acquisition of renal trafficking receptor expression, ICOS is strictly required for local inflammatory functions of autoreactive CD4 T cells in murine lupus.

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 funded by National Institutes of Health Grants AR40072, AR44076, and P30 AR033495 and by support from Rheuminations, Inc., the Arthritis Foundation, and the Connecticut Chapter of the Lupus Foundation of America.

² J.M.O. and L.D.D. contributed equally to this work.

³ Current address: Department of Immunology; MD Anderson Cancer Center; Houston, TX 77030.

⁴ Address correspondence and reprint requests to Dr. Joe Craft, Department of Internal Medicine, Section of Rheumatology, 300 Cedar Street, P.O. Box 208031, New Haven, CT 06520. E-mail address: joseph.craft{at}yale.edu

⁵ Abbreviations used in this paper: ANA, anti-nuclear Ab; BUN, blood urea nitrogen; PSGL-1, P-selectin glycoprotein receptor 1; P-selectin-L, ligand for P-selectin; AF, Alexa Fluor; FANA, fluorescent ANA; BUN, blood urea nitrogen; DC, dendritic cell; MHCII, MHC class II.