A Defect in Interleukin 12–Induced Activation and Interferon γ Secretion of Peripheral Natural Killer T Cells in Nonobese Diabetic Mice Suggests New Pathogenic Mechanisms for Insulin-Dependent Diabetes Mellitus

Abstract

The function of natural killer T (NKT) cells in the immune system has yet to be determined. There is some evidence that their defect is associated with autoimmunity, but it is still unclear how they play a role in regulating the pathogenesis of T cell–mediated autoimmune diseases. It was originally proposed that NKT cells could control autoimmunity by shifting the cytokine profile of autoimmune T cells toward a protective T helper 2 cell (Th2) type. However, it is now clear that the major function of NKT cells in the immune system is not related to their interleukin (IL)-4 secretion. In fact, NKT cells mainly secrete interferon (IFN)-γ and, activated in the presence of IL-12, acquire a strong inflammatory phenotype and cytotoxic function.

Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse

“…In the passive-transfer models, the infusion of thymic ''NKT'' cells was significantly more efficacious than those lines derived from the spleen, which conferred little or no protection on transfer (7). Moreover, in the V␣14J␣281 transgene model, only 3 of 6 founder lines (those with the most robust and largest numbers of NKT cells) were protected partially from diabetes (11).…”

“…CD1d is a nonpolymorphic class Ib protein expressed on the cell surface of antigen presenting cells, whose function is to present lipid antigens in its antigen-binding groove to CD1d-restricted T cells (3,4). A role for CD1d-restricted T cells in the progression to IDDM was suggested by the findings of quantitative and qualitative defects in these cells in both humans with type 1 diabetes (5, 6) and rodent models of IDDM-the diabetes-prone NOD mice and the BioBreeding (BB) rat (4,(7)(8)(9). Furthermore, diabetes in NOD mice can be inhibited partially through passive transfer of NKT cells enriched for CD1d-restricted T cells (10) or through the introduction of the V␣14J␣281 transgene, which increased the number of invariant CD1d-restricted cells (11).…”

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

“…83 Regulatory T cell subsets may require IFN-␥ to maintain their down-regulatory mechanisms. 95,96 In the A/J mouse, a TH2 pathogenic mechanism accounted for severe myocarditis that correlated with eosinophilic infiltrates, giant cell formation, and IgG1 and IgE antibody responses against myosin. Abrogation of myocarditis was observed when anti-IL4 was administered suggesting that TH2 immune responses were very important in development of myocarditis in the A/J mouse model of myosin-induced myocarditis.…”

Requirement for natural killer T (NKT) cells in the induction of allograft tolerance

“…Although physiological functions of NKT cells remain obscure, some studies have suggested that NKT cells can control autoimmune diseases (18)(19)(20)(21) and Th1͞Th2 cell development (22)(23)(24)(25)(26)(27), most likely by producing large amounts of IL-4 and IFN-␥ (9,13,28). In addition, it has been shown that V␣14 NKT cells exert a major effector function in IL-12-mediated tumor rejection (12).…”