Acceleration of diabetes development in CXC chemokine receptor 3 (CXCR3)-deficient NOD mice

Diabetologia. 2012 Aug;55(8):2238-45. doi: 10.1007/s00125-012-2547-8. Epub 2012 Apr 11.

Abstract

Aims/hypothesis: The aim of this study was to understand the role of CXC chemokine receptor 3 (CXCR3), a T-helper 1(Th1) type chemokine receptor, in the pathogenesis of type 1 diabetes.

Methods: We observed the incidence of diabetes in Cxcr3 homozygous knockout mice. We compared the expression pattern of various cytokines and chemokines and the frequency of FOXP3(+) cells in the pancreas and pancreatic lymph nodes from Cxcr3 ( -/- ) NOD mice and wild-type NOD mice. In addition, we observed the migration ability of CXCR3(+)CD4(+) cells to pancreatic islets upon adoptive transfer. Finally, we examined whether Cxcr3 (+) regulatory T cells (Tregs) actually suppressed the onset of diabetes in vivo.

Results: Cxcr3 ( -/- ) NOD mice developed spontaneous diabetes earlier than did wild-type NOD mice. In Cxcr3 ( -/- ) NOD mice, Tregs were more frequent in pancreatic lymph nodes and less frequent in pancreatic islets than in wild-type NOD mice. While transferred CXCR3(-)CD4(+) cells from wild-type NOD mice did not infiltrate pancreatic islets of NOD-severe combined immunodeficiency (SCID) mice, CXCR3(+)CD4(+) cells from the same mice migrated into the recipient islets and contained Forkhead box P3 (FOXP3) upon adoptive transfer. Moreover, CD4(+)CD25(+) cells from wild-type NOD mice suppressed and delayed the onset of diabetes compared with those from Cxcr3 ( -/- ) NOD mice in a cyclophosphamide-induced diabetes model system.

Conclusions/interpretation: The mechanism of accelerated diabetes onset in Cxcr3 ( -/- ) NOD mice was considered to be due to the lack of hybrid Tregs (CXCR3(+)FOXP3(+)CD4(+) cells), which could effectively migrate into and regulate Th1 inflammation in local lesions under Cxcr3 knockout conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Blood Glucose / metabolism*
  • CD4-Positive T-Lymphocytes / metabolism
  • Chemokine CXCL10 / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / physiopathology
  • Female
  • Flow Cytometry
  • Forkhead Transcription Factors / metabolism*
  • Immunohistochemistry
  • Insulin-Secreting Cells / metabolism
  • Male
  • Mice
  • Mice, Inbred NOD
  • Receptors, CXCR3 / metabolism*
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Blood Glucose
  • Chemokine CXCL10
  • Cxcl10 protein, mouse
  • Cxcr3 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Hand1 protein, mouse
  • Receptors, CXCR3