CXCL12 (SDF-1alpha) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells.
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 1alpha), 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.
Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Moran
M
Meiron
Yaniv
Y
Zohar
Rachel
R
Anunu
Gizi
G
Wildbaum
Nathan
N
Karin
D019264:Adoptive Transfer; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D016466:CHO Cells; D054377:Chemokine CXCL12 / Q000276:immunology* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D054377:Chemokine CXCL12; D017931:DNA Primers