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-10(hi) (Tr1) and IL-4(hi) (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.
Insights
Chemokine ligand CXCL11 binding to CXCR3 receptor promotes immune tolerance and treats autoimmune disease by reducing T cell inflammation. This discovery offers new therapeutic strategies for autoimmune disorders.
Area of Science:
- Immunology
- Molecular Biology
- Neuroscience
Background:
- G protein-coupled receptors (GPCRs) activate diverse signaling pathways.
- The role of GPCR ligand-specific signaling in immune regulation is largely unexplored.
- CXCR3, a chemokine receptor on CD4+ T cells, binds CXCL9, CXCL10, and CXCL11.
Purpose of the Study:
- To investigate the distinct immune regulatory roles of CXCL10 and CXCL11 binding to CXCR3.
- To evaluate the therapeutic potential of CXCL11 in a model of autoimmune disease.
Main Methods:
- Analysis of T cell polarization and signaling pathways (STATs, p70 kinase/mTOR).
- Generation and administration of a CXCL11-Ig fusion molecule.
- Assessment of disease remission and T cell infiltration in an experimental autoimmune encephalomyelitis (EAE) model.
Main Results:
- CXCL10/CXCR3 signaling drives Th1 polarization (STAT1/4/5).
- CXCL11/CXCR3 signaling induces an immunotolerizing state (IL-10/IL-4, STAT3/6).
- CXCL11-Ig treatment rapidly remitted EAE and prevented relapse, reducing T cell accumulation at the autoimmune site.
Conclusions:
- CXCL11 exhibits higher affinity for CXCR3 than CXCL10, promoting immune tolerance.
- CXCL11-Ig is a promising therapeutic agent for inflammatory autoimmune diseases like EAE.
- Targeting the CXCL11/CXCR3 axis offers a novel strategy for autoimmune disease treatment.
