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

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.