Low rate of proliferation in immature thymocytes of the non-obese diabetic mouse maps to the ldd6 diabetes susceptibility region

Aims/hypothesis. The non-obese diabetic (NOD) mouse spontaneously develops T-cell-dependent autoimmune diabetes. this mouse strain has a number of immune dysfunctions related to T-cell development but so far there are no available data on the proliferation of NOD immature thymocytes. We therefore studied the thymocyte proliferation in the NOD mouse in discrete stages of T-cell development. Methods. We depleted thymocytes in vivo and analysed thymocyte proliferation during the thymus recovery from depletion. We used co-segregation analysis and quantitative loci trait analysis to investigate the genetic control of proliferation impairments in NOD thymocytes. Results. Immature thymocytes of female NOD mice proliferate with a relatively low rate compared to non-autoimmune C571B1/6 mice. This aberrant proliferation was most pronounced in CD4(-/lo) CD8(+) cells differentiating from the CD4(-)CD8(-) to the CD4(+)CD8(+) stage. A genetic mapping study using an F2 intercross between the NOD and the C57BL/6 strains showed that a major locus controlling this trait is Linked to the insulin-dependent diabetes susceptibility locus Idd6. Conclusion/interpretation. Our results suggest that impairment of proliferation of immature thymocytes is one possible mechanism through which the Idd6 locus contributes to the pathogenesis of diabetes.