CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis
Yaniv Zohar, Gizi Wildbaum, Rostislav Novak, Andrew L. Salzman, Marcus Thelen, Ronen Alon, Yiftah Barsheshet, Christopher L. Karp, and Nathan Karin
Find articles by Zohar, Y. in: JCI | PubMed | Google Scholar
Find articles by Wildbaum, G. in: JCI | PubMed | Google Scholar
Find articles by Novak, R. in: JCI | PubMed | Google Scholar
Find articles by Salzman, A. in: JCI | PubMed | Google Scholar
Find articles by Thelen, M. in: JCI | PubMed | Google Scholar
Find articles by Alon, R. in: JCI | PubMed | Google Scholar
Find articles by Barsheshet, Y. in: JCI | PubMed | Google Scholar
Find articles by Karp, C. in: JCI | PubMed | Google Scholar
Find articles by Karin, N. in: JCI | PubMed | Google Scholar
First published March 1, 2018 - More info
J Clin Invest. 2018;128(3):1200–1201. https://doi.org/10.1172/JCI120358.
Copyright © 2018, American Society for Clinical Investigation
Related article:
Abstract
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.
Authors
Yaniv Zohar, Gizi Wildbaum, Rostislav Novak, Andrew L. Salzman, Marcus Thelen, Ronen Alon, Yiftah Barsheshet, Christopher L. Karp, Nathan Karin
Original citation: J Clin Invest. 2014;124(5):2009–2022. https://doi.org/10.1172/JCI71951
Citation for this corrigendum: J Clin Invest. 2018;128(3):1200–1201. https://doi.org/10.1172/JCI120358
The Editors recently posted an Expression of Concern for this article due to duplication of some of the flow cytometry plots in Figures 5C and 7A (1). The authors have completed three replicate experiments for the panels in question, and the updated findings appear below. The revised experiments were conducted by Yaniv Zohar, and the analysis was completed independently in a blinded fashion. The authors report in Figure 5C that repeated administration of CXCL11-Ig increased the in vivo polarization of IL-10hi CD4+ T cells, suggesting that CXCL11 supports Tr1 polarization. In addition, the authors state that Experiments 1 and 2 suggest that the administration of CXCL10-Ig induced IFNhi Th1 cells, consistent with the notion of the differential functions of CXCL10 and CXCL11 in T cell polarization. This finding was not confirmed in Experiment 3.
Figure 7A shows reduced accumulation of injected CD4+ T cells in the draining LN and spinal cord, but not the spleen, consistent with the original findings of the article.
The authors regret the errors and appreciate the opportunity to correct the article.
1. J Clin Invest. 2017;127(10):3913. https://doi.org/10.1172/JCI97015
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)