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CXCL12 (SDF-1) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells

¹ Department of Immunology and ² Rappaport Family Institute for Research in the Medical Sciences and Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel

CORRESPONDENCE Nathan Karin: nkarin{at}tx.technion.ac.il

Experimental autoimmune encephalomyelitis (EAE) is a T cell–mediated autoimmune disease of the central nervous system induced by antigen-specific effector Th17 and Th1 cells. We show that a key chemokine, CXCL12 (stromal cell–derived factor 1), redirects the polarization of effector Th1 cells into CD4⁺CD25^–Foxp3^–interleukin (IL) 10^high antigen-specific regulatory T cells in a CXCR4-dependent manner, and by doing so acts as a regulatory mediator restraining the autoimmune inflammatory process. In an attempt to explore the therapeutic implication of these findings, we have generated a CXCL12-immunoglobulin (Ig) fusion protein that, when administered during ongoing EAE, rapidly suppresses the disease in wild-type but not IL-10–deficient mice. Anti–IL-10 neutralizing antibodies could reverse this suppression. The beneficial effect included selection of antigen-specific T cells that were CD4⁺CD25^–Foxp3^–IL-10^high, which could adoptively transfer disease resistance, and suppression of Th17 selection. However, in vitro functional analysis of these cells suggested that, even though CXCL12-Ig–induced tolerance is IL-10 dependent, IL-10–independent mechanisms may also contribute to their regulatory function. Collectively, our results not only demonstrate, for the first time, that a chemokine functions as a regulatory mediator, but also suggest a novel way for treating multiple sclerosis and possibly other inflammatory autoimmune diseases.

Abbreviations used: CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; PI, propidium iodide; SDF-1, stromal cell–derived factor 1.

M. Meiron and Y. Zohar contributed equally to this paper.

© 2008 Meiron et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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