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

Marika Falcone, Brian Yeung, Lee Tucker, Enrique Rodriguez, Nora Sarvetnick

Research output: Contribution to journalArticle

122 Scopus citations

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. In this study, we have focused our attention on peripheral, IFN-γ-secreting NKT cells of nonobese diabetic (NOD) mice and their ability to immunomodulate the pathogenesis of insulin-dependent diabetes mellitus (IDDM). We found that in NOD mice, the lack of immunoregulatory function of NKT cells in vivo correlated with a dramatic defect in proliferation and differentiation toward an IFN-γ-secreting phenotype upon T cell receptor engagement and IL-12 stimulation. Peripheral NKT cells may have a critical role balancing inflammatory immune responses and avoiding autoimmunity, such that the functional defect we found in the NOD mice may ultimately result in autoimmunity through inadequate counterregulation of the immune response.

Original languageEnglish (US)
Pages (from-to)963-972
Number of pages10
JournalJournal of Experimental Medicine
Volume190
Issue number7
DOIs
StatePublished - Oct 4 1999
Externally publishedYes

Keywords

  • Autoimmunity
  • Interferon γ
  • Interleukin 4
  • Natural killer T cells
  • Regulatory cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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