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

Y. Yamada, Y. Okubo, A. Shimada, Y. Oikawa, S. Yamada, S. Narumi, K. Matsushima, H. Itoh

Research output: Contribution to journalReview articlepeer-review

26 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2238-2245
Number of pages8
JournalDiabetologia
Volume55
Issue number8
DOIs
Publication statusPublished - 2012 Aug

Keywords

  • CXCR3
  • Hybridtreg
  • Nodmouse
  • Regulatory tcell
  • Type 1 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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