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, Nathan Karin
Yaniv Zohar, Gizi Wildbaum, Rostislav Novak, Andrew L. Salzman, Marcus Thelen, Ronen Alon, Yiftah Barsheshet, Christopher L. Karp, Nathan Karin
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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 7

Effects of CXCL11 therapy on CD4+ T cell recruitment and EAE suppression.

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Effects of CXCL11 therapy on CD4+ T cell recruitment and EAE suppression...
(A) CXCL11-Ig–based therapy affected recruitment of CD4+ T cells to the CNS and cervical LN, but not the spleen, of EAE mice. CD3+ T cells from donor GFP–β-actin reporter EAE mice were purified (MACs MicroBeads) and directly transferred to recipient WT mice (20 × 106 cells/mouse) at disease onset (day 11). These mice were then treated (days 11 and 13) with CXCL11-Ig (100 μg/mouse), PBS, or isotype-matched IgG. On day 14, recipient mice were sacrificed, and cervical LN, spinal cord (SC), and spleen cells were analyzed for relative donor CD4+ T cell accumulation. Shown are data from a single representative mouse (see Supplemental Figure 2 for comprehensive analysis of all mice). (B) Low-dose administration of CXCL11 preferentially suppressed EAE in C57BL/6 mice. At disease onset, C57BL/6 and SJL/J mice were subjected on alternating days to low-dose administration of 4 or 40 μg/kg BW of CXCL11 (R&D) (∼0.08 and ∼0.8 μg/mouse, respectively) and followed for disease development and progression. Data (mean ± SEM) are from 1 of 3 independent experiments with similar results. *P < 0.001.