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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901340v1 183/4/2321    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Raveney, B. J. E. Articles by Nicholson, L. B. PubMed PubMed Citation Articles by Raveney, B. J. E. Articles by Nicholson, L. B.

TNFR1-Dependent Regulation of Myeloid Cell Function in Experimental Autoimmune Uveoretinitis¹

Ben J. E. Raveney^2,*, David A. Copland, Andrew D. Dick^*, and Lindsay B. Nicholson^3,*,

^* Department of Cellular and Molecular Medicine, School of Medical Sciences and Unit of Ophthalmology, Department of Clinical Sciences at South Bristol, University of Bristol, Bristol, United Kingdom

Experimental autoimmune uveoretinitis is an autoimmune disease induced in mice, which involves the infiltration of CD11b⁺ macrophages and CD4⁺ T cells into the normally immune-privileged retina. Damage is produced in the target organ following the activation of Th1 and Th17 T cells and by the release of cytotoxic mediators such as NO by activated macrophages. The majority of immune cells infiltrating into the retina are CD11b⁺ myeloid cells, but, despite the presence of these APCs, relatively limited numbers of T cells are observed in the retina during the disease course. These T cells do not proliferate when leukocytes are isolated from the retina and restimulated in vitro, although they do produce both IFN- and IL-17. T cell proliferation was restored by depleting the myeloid cells from the cultures and furthermore those isolated myeloid cells were able to regulate the proliferation of other T cells. The ability of macrophages to regulate proliferation depends on activation by T cell-produced IFN- and autocrine TNF- signaling in the myeloid cells via TNFR1. In the absence of TNFR1 signaling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo. However, TNFR1 signaling is also required for macrophages, but not T cells, to migrate into the target organ. Thus, in TNFR1 knock out mice, the amplification of autoimmunity is limited, leading to resistance to experimental autoimmune uveoretinitis induction.

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 the National Eye Research Centre, U.K.

² Current address: Department of Immunology, National Institute of Neuroscience NCNP, Tokyo, Japan.

³ Address correspondence and reprint requests to Dr. L. B. Nicholson, Reader in Research, University of Bristol, Department of Cellular and Molecular Medicine, School of Medical Sciences, University Walk, Bristol, U.K. E-mail address: l.nicholson{at}bristol.ac.uk

⁴ Abbreviations used in this paper: EAU, experimental autoimmune uveoretinitis; RBP, retinol binding protein; MTb, Mycobacterium tuberculosis; WT, wild type; iNOS, inducible NO synthase; MDSC, myeloid-derived supressor cell.