Thymic and peripheral T-cells from NOD mice display a proliferative unresponsiveness on stimulation through the T-cell receptor/CD3 complex. Interleukin 4 reverses NOD T-cell unresponsiveness in vitro and prevents the onset of diabetes in vivo, suggesting a causal relationship between the T-cell unresponsiveness and diabetes susceptibility in NOD mice. Both quantitative trait loci analysis of BXD recombinant inbred mice and linkage analysis of NOD outcross populations reveal that the control of NOD thymic T-cell proliferative unresponsiveness genetically maps to a central region on mouse chromosome 11, which includes the β-chemokine gene family. This finding raises the possibility that a β-chemokine(s) may regulate T-cell unresponsiveness as well as diabetes susceptibility in NOD mice.