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.
View: Text | PDF | Corrigendum | Expression of Concern
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

×

Figure 6

CXCL11 redirects the polarization of effector T cells into IL-10hi Tr1 cells and provides long-lasting EAE resistance.

Options: View larger image (or click on image) Download as PowerPoint
CXCL11 redirects the polarization of effector T cells into IL-10hi Tr1 c...
(A) CD4+ T cells from pre-EAE mice (day 9) were activated with target antigen and 20 ng/ml CXCL11 or CXCL10 (R&D; added 24 hours later). 48 hours later, CD4+ T cells were separated (MACs MicroBeads) and analyzed for IL-4 and IL-10 production. (B) 20 × 106 of these cells were transferred to SJL/J EAE mice at disease onset. (C) Recipient mice (6 per group) administered CD4+ T cells from CXCL11-Ig–treated donors were repeatedly injected with anti–IL-4 or anti–IL-10 neutralizing mAbs (PeproTec; 100 μg/mouse) or PBS. (D) SJL/J EAE mice were administered anti–IL-10, isotype-matched IgG, or PBS on day 9. (E) Donor C57BL/6 WT or Il10–/– mice were immunized with MOG35–55/CFA to induce EAE. On days 3, 5, 7, and 9, mice were treated with CXCL11-Ig (100 μg/mouse) or PBS. On day 11, CD4+ T cells were isolated and 20 × 106 were transferred to WT EAE mice (6 per group). (F) EAE was induced in SJL/J mice. At disease onset, mice were separated into 3 groups (10 per group); treated every other day with CXCL11-Ig, CXCL10-Ig, or isotype-matched IgG (100 μg/mouse); and followed for progression of the first EAE episode and development of a second episode. Data (mean ± SEM) are from 1 of 3 (B, C, and F) or 2 (D and E) independent experiments with similar results. †P < 0.05, #P < 0.01, *P < 0.001.