CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis
Yaniv Zohar, … , Christopher L. Karp, Nathan Karin
Yaniv Zohar, … , Christopher L. Karp, Nathan Karin
Published April 8, 2014
Citation Information: J Clin Invest. 2014;124(5):2009-2022. https://doi.org/10.1172/JCI71951.
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Research Article

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

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

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Figure 3

CXCL10 and CXCL11 polarize Th1 and Tr1 by inducing diverse STAT-dependent pathways.

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CXCL10 and CXCL11 polarize Th1 and Tr1 by inducing diverse STAT-dependen...
CD4+ T cells were isolated from LNs of naive mice (MACs MicroBeads) and activated with anti-CD3/anti-CD28; 24 hours later, cultures were supplemented with CXCL10 or CXCL11 (100 ng/ml, R&D). (A) After 1, 5, and 15 minutes, cells were subjected to flow cytometry for various STAT proteins. (B and C) After 0, 10, 30, and 60 minutes, cells were subjected to Western blot analysis comparing the phosphorylation level of various STAT proteins (B) or of other intracellular mediators, including Akt, p70S6K, and mTOR (C). Results shown in B and C are from the same experiment; separation was done only for didactical reasons.