First published August 28, 2017 - More info
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.
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 expression of concern: J Clin Invest. 2017;127(10):3913. https://doi.org/10.1172/JCI97015
The Editors recently became aware that some of the flow cytometry plots in this article were duplicated and used to represent different samples. Specifically, in Figure 5C, the flow cytometry plots of IFN-γ– and IL-17–stained cells from IgG1- and CXCL10-Ig–treated animals are from the same sample. In addition, in Figure 7A, the spinal cord samples from the PBS- and IgG1-treated animals are the same; the spleen samples from the CXCL11-Ig– and IgG1–treated animals are the same; and the lymph node samples for the PBS- and IgG1-treated animals are the same. The authors were unable to provide the original data for these figures. The Journal subsequently requested an institutional investigation by the Technion – Israel Institute of Technology, which was recently completed. The investigative committee concluded that identical data were presented twice in the publication and that the raw data were not archived for the amount of time required by Technion. The authors have stated that the errors were unintentional.
The Editorial Board is issuing this Expression of Concern to alert readers to the problems identified in Figures 5C and 7A. The Editors have requested that the experiments in question be repeated by the authors and resubmitted to the Journal. We will inform our readers of the outcome after the data have been evaluated.
See the related article at CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis.