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

PLoS One. 2015 May 6;10(5):e0126311. doi: 10.1371/journal.pone.0126311. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoimmunity / immunology
  • Cell Movement / immunology
  • Chemokine CXCL10 / metabolism
  • Chemokine CXCL11 / metabolism
  • Chemokine CXCL9 / metabolism
  • Diabetes Mellitus, Type 1 / immunology*
  • Inducible T-Cell Co-Stimulator Protein / metabolism*
  • Insulin-Secreting Cells / immunology
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / immunology
  • Interleukin-2 / deficiency
  • Interleukin-2 / immunology
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Prediabetic State / immunology
  • Receptors, CXCR3 / biosynthesis*
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / transplantation
  • Th1 Cells / immunology*
  • Th1 Cells / transplantation

Substances

  • Chemokine CXCL10
  • Chemokine CXCL11
  • Chemokine CXCL9
  • Cxcl10 protein, mouse
  • Cxcl11 protein, mouse
  • Cxcl9 protein, mouse
  • Cxcr3 protein, mouse
  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-2
  • Receptors, CXCR3
  • Interferon-gamma