title: Th1-Like ICOS+ Foxp3+ Treg 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 (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.
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada, H3A 2B4.
authors.forename: Mara
authors.initials: M
authors.lastname: Kornete
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada, H3A 2B4.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Mason
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada, H3A 2B4.
authors.forename: Julien
authors.initials: J
authors.lastname: Girouard
authors.affiliation: Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Erin I
authors.initials: EI
authors.lastname: Lafferty
authors.affiliation: Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Salman
authors.initials: S
authors.lastname: Qureshi
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada, H3A 2B4; Microbiome and Disease Tolerance Centre, McGill University, Montreal, QC, Canada, H3A 2B4; FOCIS Center of Excellence in Translational Immunology, Research Institute of the McGill University Health Centre, Montreal, QC, Canada, H3G 1A4.
authors.forename: Ciriaco A
authors.initials: CA
authors.lastname: Piccirillo
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054357:Chemokine CXCL10 / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000172:deficiency / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011236:Prediabetic State / Q000276:immunology; D054367:Receptors, CXCR3 / Q000096:biosynthesis*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology* / Q000637:transplantation
chemical_list: D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; C485433:Cxcl10 protein, mouse; C515203:Cxcl11 protein, mouse; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2; D054367:Receptors, CXCR3; D007371:Interferon-gamma