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 (Treg) 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 Treg 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 Treg cells in situ. Here, we propose an ICOS-dependent mechanism of Treg cell homing to the β-islets during pre-diabetes in the NOD model via upregulation of the CXCR3 chemokine receptor. The islet-specific ICOS+ Treg cell subset preferentially expresses CXCR3 in the pancreatic lymph nodes (pLN) in response to Teff cell-mediated pancreatic inflammation, an expression correlating with the onset and magnitude of IFN-γ production by Teff 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+ Treg cell chemotaxis in vitro. Strikingly, islet-derived Treg cells also produce these chemokines suggesting an auto-regulation of homing by this subset. Unlike ICOS- cells, ICOS+ Treg cells adopt a Th1-like Treg 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 Treg cell CXCR3 upregulation evincing its role in regulating expression of this chemokine receptor by Treg cells. Thus, CXCR3-mediated trafficking of Treg cells could represent a mechanism of homeostatic immunoregulation during diabetogeneesis.
Highlights
Mechanisms of peripheral immune self-tolerance prevent the onset and progression of pathological autoimmune responses
We previously showed that ICOS+ T regulatory (Treg) cells, compared to ICOS- Treg cells, display an increased functionally fit phenotype and preferentially accumulate in pre-diabetic islets of BDC2.5 non-obese diabetic (NOD) mice [7]
We found that in contrast to other T cell subsets, ICOS+ Treg cells displayed marked CXCR3 expression in the draining pancreatic lymph nodes (pLN) of pre-diabetic BDC2.5 NOD mice
Summary
Mechanisms of peripheral immune self-tolerance prevent the onset and progression of pathological autoimmune responses. In order to establish and maintain dominant self-tolerance, Treg cells employ a plethora of immunosuppressive mechanisms including production of anti-inflammatory cytokines like TGF-β and IL-10, thereby inhibiting Teff cell expansion and effector functions. Developmental blockade of this lineage in mice via day 3 thymectomy provokes lympho-proliferative and multi-organ autoimmune disease [1]. IFN-γ produced by islet-reactive Teff cells in vivo induces expression of CXCR3 by ICOS+ Treg cells and correlates with the onset and magnitude of inflammation in pancreatic sites. This data indicates trafficking of Treg cells represents a mechanism of homeostatic regulation of autoimmunity in T1D
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