NK T cell-induced protection against diabetes in V alpha 14-J alpha 281 transgenic nonobese diabetic mice is associated with a Th2 shift circumscribed regionally to the islets and functionally to islet autoantigen

J Immunol. 2001 Mar 15;166(6):3749-56. doi: 10.4049/jimmunol.166.6.3749.

Abstract

The onset of autoimmune diabetes is related to defective immune regulation. Recent studies have shown that NK T cells are deficient in number and function in both diabetic patients and nonobese diabetic (NOD) mice. NK T cells, which are CD1d restricted, express a TCR with an invariant V alpha 14-J alpha 281 chain and rapidly produce large amounts of cytokines. V alpha 14-J alpha 281 transgenic NOD mice have increased numbers of NK T cells and are protected against diabetes onset. In this study we analyzed where and how NK T cells interfere with the development of the anti-islet autoimmune response. NK T cells, which are usually rare in lymph nodes, are abundant in pancreatic lymph nodes and are also present in islets. IL-4 mRNA levels are increased and IFN-gamma mRNA levels decreased in islets from diabetes-free V alpha 14-J alpha 281 transgenic NOD mice; the IgG1/IgG2c ratio of autoantibodies against glutamic acid decarboxylase is also increased in these mice. Treatment with IL-12 (a pro-Th1 cytokine) or anti-IL-4 Ab abolishes the diabetes protection in V alpha 14-J alpha 281 NOD mice. The protection from diabetes conferred by NK T cells is thus associated with a Th2 shift within islets directed against autoantigen such as glutamic acid decarboxylase. Our findings also demonstrate the key role of IL-4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / administration & dosage
  • Antibodies, Monoclonal / administration & dosage
  • Autoantigens / immunology*
  • Cytokines / biosynthesis
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / prevention & control*
  • Female
  • Glutamate Decarboxylase / immunology
  • Immunoglobulin Isotypes / biosynthesis
  • Immunosuppressive Agents / administration & dosage
  • Injections, Intraperitoneal
  • Interferon-gamma / biosynthesis
  • Interleukin-10 / physiology
  • Interleukin-12 / administration & dosage
  • Interleukin-4 / biosynthesis
  • Interleukin-4 / physiology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / metabolism
  • Isoenzymes / immunology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Lymphocyte Count
  • Lymphoid Tissue / cytology
  • Lymphoid Tissue / immunology
  • Mice
  • Mice, Congenic
  • Mice, Inbred NOD
  • Mice, Transgenic
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / immunology*
  • Th2 Cells / immunology*
  • Th2 Cells / metabolism*

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Autoantigens
  • Cytokines
  • Immunoglobulin Isotypes
  • Immunosuppressive Agents
  • Isoenzymes
  • Interleukin-10
  • Interleukin-12
  • Interleukin-4
  • Interferon-gamma
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2