Intrinsic Defects in the T-Cell Lineage Results in Natural Killer T-Cell Deficiency and the Development of Diabetes in the Nonobese Diabetic Mouse

Abstract

T-cell–mediated autoimmune diabetes in nonobese diabetic (NOD) mice is closely associated with natural killer T (NKT)-cell deficiency. To determine whether intrinsic defects of the T-cell lineage contribute to the pathogenesis of the disease and NKT cell deficiency, we reconstituted the T-cell compartment in NOD.scid or BALB.scid mice with T-cells from NOD, nonobese diabetes-resistant (NOR), or AKR thymic precursor cells and examined the development of the NKT cell population. NKT cells developed well from AKR thymic precursor cells but not from other precursor cells in both recipient strains. Insulitis and diabetes developed only in the NOD.scid recipients of NOD or NOR precursor cells. When thymic precursor cells of β2-microglobulin gene–deficient AKR mice, which have a deficient NKT population, were introduced into NOD.scid recipients, both CD4⁺ and CD8⁺ T-cell populations developed and the recipient mice developed insulitis and diabetes. We conclude that NKT cells originate from a T-cell–committed thymic precursor population and that the deficiency in the NKT cell population in NOD mice results from intrinsic defects within the T-cell lineage and plays a major role in the development of autoimmune diabetes in the presence of both the NOD thymus and antigen-presenting cells.