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

Abstract

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 1α), redirects the polarization of effector Th1 cells into CD4+CD25−Foxp3−interleukin (IL) 10high 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-10high, 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.

A Fusion Protein Encoding the Second Extracellular Domain of CCR5 Arrests Chemokine-Induced Cosignaling and Effectively Suppresses Ongoing Experimental Autoimmune Encephalomyelitis

“…On this subject, we have previously shown that of the different CXCR3 ligands CXCL10, but not CXCL11, polarizes CD4 + T cells to effector Th1 and, by doing so, promotes the development and progression of different inflammatory autoimmune diseases and makes this chemokine an attractive target for therapy of these diseases (15,16). More recently, we have shown that the chemokine CXCL12 (SDF-1a) functions as an anti-inflammatory chemokine that polarizes macrophages to become IL-10-producing anti-inflammatory macrophages (17), also known as M2 macrophages (39), and Ag-specific T cells, to become IL-10-producing regulatory T cells (17), also known as Tr1 (40).…”

“…For example, the CXCR3 ligand CXCL10 polarizes CD4 + T cells into effector Th1 (15,16), whereas CXCL12 skews T cell polarization into IL-10-producing Ag-specific regulatory T cells (17). Another example for the variety of biological properties of chemokines is their role in the activation of adhesion receptors, an essential step allowing rapid influx of leukocytes to target organs (18,19).…”

Inhibition of Hyaluronan Synthesis Protects against Central Nervous System (CNS) Autoimmunity and Increases CXCL12 Expression in the Inflamed CNS

“…(iii) CXCL12 attracts immature dendritic cells with anti-inflammatory properties into the CNS (36). (iv) Finally, CXCL12 is able to redirect already differentiated Th1 cells into anti-regulatory T-cells (29). We showed that inhibition of CXCR4 by the application of AMD3100 neutralized the protective impact of 4MU on passive EAE in C57Bl/6 mice, suggesting that hyaluronan augments CNS autoimmunity by suppressing CXCL12 production in the CNS.…”

Inhibition of CXCL12 Signaling Attenuates the Postischemic Immune Response and Improves Functional Recovery after Stroke

“…25 The action of CXCL12 is not unambiguous. CXCL12 is instrumental in attracting CXCR4-expressing immune cells to tissues, aggravating tissue injury, 26 while in demyelinating inflammatory conditions 27 or infectious disease such as West Nile virus encephalitis, CXCL12 prevents the entry of cluster of differentiation 8-positive (CD8 þ ) cells into the brain at the brain-endothelial interface and therefore appears to have a protective function. 28 This study was undertaken to analyze how multisensory stimulation of the brain that improves brain function after experimental stroke, affect inflammatory processes in the brain.…”