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

121 Citations (Scopus)

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

Fingerprint

Inbred NOD Mouse
Natural Killer T-Cells
Interleukin-12
Type 1 Diabetes Mellitus
Interferons
Autoimmunity
Immune System
T-Lymphocytes
Phenotype
Th2 Cells
T-Cell Antigen Receptor
Interleukin-4
Autoimmune Diseases
Cytokines

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

@article{2f7ba64293714d6da83b201b37f437f0,
title = "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. 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.",
keywords = "Autoimmunity, Interferon γ, Interleukin 4, Natural killer T cells, Regulatory cells",
author = "Marika Falcone and Brian Yeung and Lee Tucker and Enrique Rodriguez and Nora Sarvetnick",
year = "1999",
month = "10",
day = "4",
doi = "10.1084/jem.190.7.963",
language = "English (US)",
volume = "190",
pages = "963--972",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "7",

}

TY - JOUR

T1 - 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

AU - Falcone, Marika

AU - Yeung, Brian

AU - Tucker, Lee

AU - Rodriguez, Enrique

AU - Sarvetnick, Nora

PY - 1999/10/4

Y1 - 1999/10/4

N2 - 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.

AB - 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.

KW - Autoimmunity

KW - Interferon γ

KW - Interleukin 4

KW - Natural killer T cells

KW - Regulatory cells

UR - http://www.scopus.com/inward/record.url?scp=0033523666&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033523666&partnerID=8YFLogxK

U2 - 10.1084/jem.190.7.963

DO - 10.1084/jem.190.7.963

M3 - Article

C2 - 10510086

AN - SCOPUS:0033523666

VL - 190

SP - 963

EP - 972

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 7

ER -