Journal article

CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis

  • Zohar, Yaniv Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
  • Wildbaum, Gizi Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
  • Novak, Rostislav Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
  • Salzman, Andrew L. Radikal Therapeutics Inc., West Tisbury, Massachusetts, USA
  • Thelen, Marcus Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Alon, Ronen Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
  • Barsheshet, Yiftah Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
  • Karp, Christopher L. Division of Cellular and Molecular Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  • Karin, Nathan Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel - Rappaport Family Institute for Research in the Medical Sciences and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
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    08.04.2014
Published in:
  • The journal of clinical investigation. - 2014, vol. 124, no. 5, p. 2009-2022
English A single G protein–coupled receptor (GPCR) can activate multiple signaling cascades based on the binding of different ligands. The biological relevance of this feature in immune regulation has not been evaluated. The chemokine-binding GPCR CXCR3 is preferentially expressed on CD4+ T cells, and canonically binds 3 structurally related chemokines: CXCL9, CXCL10, and CXCL11. Here we have shown that CXCL10/CXCR3 interactions drive effector Th1 polarization via STAT1, STAT4, and STAT5 phosphorylation, while CXCL11/CXCR3 binding induces an immunotolerizing state that is characterized by IL-10hi (Tr1) and IL-4hi (Th2) cells, mediated via p70 kinase/mTOR in STAT3- and STAT6-dependent pathways. CXCL11 binds CXCR3 with a higher affinity than CXCL10, suggesting that CXCL11 has the potential to restrain inflammatory autoimmunity. We generated a CXCL11-Ig fusion molecule and evaluated its use in the EAE model of inflammatory autoimmune disease. Administration of CXCL11-Ig during the first episode of relapsing EAE in SJL/J mice not only led to rapid remission, but also prevented subsequent relapse. Using GFP-expressing effector CD4+ T cells, we observed that successful therapy was associated with reduced accumulation of these cells at the autoimmune site. Finally, we showed that very low doses of CXCL11 rapidly suppress signs of EAE in C57BL/6 mice lacking functional CXCL11.
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  • English
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Biology
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https://susi.usi.ch/usi/documents/318977
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