Th1-Like ICOS ⁺ Foxp3 ⁺ T _reg Cells Preferentially Express CXCR3 and Home to β-Islets during Pre-Diabetes in BDC2.5 NOD Mice

Abstract

Type 1 diabetes (T1D) occurs through a breakdown of self-tolerance resulting in the autoimmune destruction of the insulin producing β-islets of the pancreas. A numerical and functional waning of CD4 ⁺Foxp3 ⁺ regulatory T (T _reg) cells, prompted by a pancreatic IL-2 deficiency, accompanies Th1 autoimmunity and T1D progression in non-obese diabetic (NOD) mice. Recently, we identified a dominant subset of intra-islet T _reg cells that expresses the ICOS costimulatory receptor and promotes self-tolerance delaying the onset of T1D. ICOS co-stimulation potently enhances IL-2 induced survival and proliferation, and suppressive activity of T _reg cells in situ. Here, we propose an ICOS-dependent mechanism of T _reg cell homing to the β-islets during pre-diabetes in the NOD model via upregulation of the CXCR3 chemokine receptor. The islet-specific ICOS ⁺ T _reg cell subset preferentially expresses CXCR3 in the pancreatic lymph nodes (pLN) in response to T _eff cell-mediated pancreatic inflammation, an expression correlating with the onset and magnitude of IFN-γ production by T _eff cells in pancreatic sites. We also reveal that intra-pancreatic APC populations and insulin-producing β, but not α nor δ, islet cells secrete the CXCR3 chemokines, CXCL9, 10 and 11, and selectively promote ICOS ⁺CXCR3 ⁺ T _reg cell chemotaxis in vitro. Strikingly, islet-derived T _reg cells also produce these chemokines suggesting an auto-regulation of homing by this subset. Unlike ICOS ^- cells, ICOS ⁺ T _reg cells adopt a Th1-like T _reg phenotype while maintaining their suppressive capacity, characterized by expression of T-bet and CXCR3 and production of IFN-γ in the draining pLNs. Finally, in vivo neutralization of IFN-γ blocked T _reg cell CXCR3 upregulation evincing its role in regulating expression of this chemokine receptor by T _reg cells. Thus, CXCR3-mediated trafficking of T _reg cells could represent a mechanism of homeostatic immunoregulation during diabetogeneesis.