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.

Chemokine receptor CXCR3 deficiency exacerbates murine autoimmune cholangitis by promoting pathogenic CD8+ T cell activation

“…Second, chemokines expressed in specific lymphoid compartments may influence more globally the positioning of T cells in particular microenvironments, to bring these cells in contact with the appropriate APCs or accessory cells important for their differentiation [9, 37, 38]. Chemokine receptors are 7-transmembrane GPCRs, and thus may transmit diverse signaling cascades upon binding to different ligands to determine T cell fate [10]. Specifically, CXCL10/CXCR3 interactions drive effector Th1 polarization via STAT1, STAT4, and STAT5 phosphorylation, while CXCL11/CXCR3 binding induces an immune-tolerizing state characterized by IL-10 hi (Tr1) and IL-4 hi (Th2) cells, mediated via p70 kinase/mTOR in STAT3- and STAT6-dependent pathways [10].…”

“…Chemokine receptors are 7-transmembrane GPCRs, and thus may transmit diverse signaling cascades upon binding to different ligands to determine T cell fate [10]. Specifically, CXCL10/CXCR3 interactions drive effector Th1 polarization via STAT1, STAT4, and STAT5 phosphorylation, while CXCL11/CXCR3 binding induces an immune-tolerizing state characterized by IL-10 hi (Tr1) and IL-4 hi (Th2) cells, mediated via p70 kinase/mTOR in STAT3- and STAT6-dependent pathways [10]. …”

“…CXCR3 expression on T cells alters the balance between effector and memory CD8+ T cell generation [9]. Finally, the CXCL11-CXCR3 chemokine axis polarizes naive T cells and repolarizes effector CD4+ T cells into IL-10 hi Tr1 cells to induce an immune-tolerizing state [10]. Our lab has been studying the pathogenesis of human PBC and during the course of these studies reported significant increases in the levels of soluble IP-10 (CXCL10) and MIG (CXCL9) in PBC and also a marked increase in the frequency of CXCR3 expressing T cells in both blood and liver [11].…”

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model

“…Intriguingly, the distinct functional outcomes elicited by CXCL10 and CXCL11 downstream of CXCR3 can drive opposing cellular and physiologic consequences. For instance, CXCL11 signaling promotes Th1 cell polarization into an immunotolerant T cell subset, resulting in an anti-inflammatory phenotype in a mouse model of multiple sclerosis, whereas CXCL10 promotes pro-inflammatory effects [105]. …”

Amelioration of patients with chronic spontaneous urticaria in treatment with vitamin D supplement

“…The data were aligned with other studies focused on the phenotype or functional analysis of Tregs, they had revealed Treg which isolated from patients with autoimmune disorder reduced regulatory function comparing with healthy individual Tregs [17]. Treg devoted to aiding immune tolerance, hence their expansion is necessary for the resolution of inflammation and in preventing tissue damage or autoimmunity [18]. Tregs are usually characterized by the expression of FOXP3, which is the main transcription factor and also a master regulator of the immune suppressive activity of Treg [19].…”