title: Acceleration of diabetes development in CXC chemokine receptor 3 (CXCR3)-deficient NOD mice.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: Y
authors.initials: Y
authors.lastname: Okubo
authors.forename: A
authors.initials: A
authors.lastname: Shimada
authors.forename: Y
authors.initials: Y
authors.lastname: Oikawa
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: S
authors.initials: S
authors.lastname: Narumi
authors.forename: K
authors.initials: K
authors.lastname: Matsushima
authors.forename: H
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D054367:Receptors, CXCR3 / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D054357:Chemokine CXCL10; D051858:Forkhead Transcription Factors; D054367:Receptors, CXCR3; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; C498833:Foxp3 protein, mouse; C095572:Hand1 protein, mouse