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 5

CXCL11-Ig suppresses ongoing EAE while selecting IL-10hi Tregs that transfer disease suppression.

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CXCL11-Ig suppresses ongoing EAE while selecting IL-10hi Tregs that tran...
(A) CXCL11-Ig suppressed ongoing EAE. EAE was induced in SJL/J mice. At disease onset, mice were separated into 4 groups of 6 each and treated every other day with CXCL11-Ig, CXCL10-Ig, control IgG1 (100 μg/mouse i.p.), or PBS and followed for the progression of the first episode of EAE by an observer blinded to the experimental protocol. (B) Histological analyses and IL-10 IHC in lumbar spinal cords of representative mice at day 19 (disease peak). Original magnification, ×40 (naive); ×100 (all other H&E); ×400 (all other IHC). See Table 1 for histological scores. (C) Disease suppression was associated with skewing CD4+ T cell subsets into IL-10hi and IL-4hi phenotype. At the peak of disease, CD3+CD4+ T cells from the CNS of each group were subjected to flow cytometry analysis of IFN-γ, IL-4, IL-17, and IL-10. (D) CD4+ T cells from protected mice transferred disease suppression. Adoptive transfer of CD4+ T cells from EAE donors treated with CXCL11-Ig, CXCL10-Ig, control IgG, or PBS to recipient EAE mice was performed at onset of active disease. Prior to transfer, levels of key cytokines were determined (see Table 2), after in vitro activation with target antigen. Data (mean ± SEM of triplicates) are from 1 of 3 independent experiments with similar results. *P < 0.001.