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

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.