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Molecular role of TGF-beta, secreted from a new type of CD4+ suppressor T cell, NY4.2, in the prevention of autoimmune IDDM in NOD mice.

Authors
Han, HS; Jun, HS; Utsugi, T; Yoon, JW
Citation
Journal of autoimmunity, 10(3):299-307, 1997
Journal Title
Journal of autoimmunity
ISSN
0896-84111095-9157
Abstract
A new type of CD4+ T cell clone (NY4.2) isolated from pancreatic islet-infiltrated lymphocytes of acutely diabetic non-obese diabetic (NOD) mice prevents the development of insulin-dependent diabetes mellitus (IDDM) in NOD mice, as well as the recurrence of autoimmune diabetes in syngeneic islet-transplanted NOD mice. It has been demonstrated that the cytokine TGF-beta, secreted from the cells of this clone, is the substance which prevents autoimmune IDDM. This investigation was initiated to determine the molecular role TGF-beta plays in the prevention of autoimmune IDDM by determining its effect on IL-2-induced signal transduction in Con A-activated NOD mouse splenocytes and HT-2 cells. First, we determined whether TGF-beta, secreted from NY4.2 T cells, inhibits IL-2-dependent T cell proliferation in HT-2 cells (IL-2-dependent T cell line) and NOD splenocytes. We found that TGF-beta suppresses IL-2-dependent T cell proliferation. Second, we determined whether TGF-beta inhibits the activation of Janus kinases (JAKs), as well as signal transducers and activators of transcription (STAT) proteins, involved in an IL-2-induced signalling pathway that normally leads to the proliferation of T cells. We found that TGF-beta inhibited tyrosine phosphorylation of JAK1, JAK3, STAT3 and STAT5 in Con A blasts from NOD splenocytes and HT-2 cells. Third, we examined whether TGF-beta inhibits the cooperation between STAT proteins and mitogen-activated protein kinase (MAPK), especially extracellular signal-regulated kinase 2 (ERK2). We found that TGF-beta inhibited the association of STAT3 and STAT5 with ERK2 in Con A blasts from NOD splenocytes and HT-2 cells. On the basis of these observations, we conclude that TGF-beta may interfere with signal transduction via inhibition of the IL-2-induced JAK/STAT pathway and inhibition of the association of STAT proteins with ERK2 in T cells from NOD splenocytes, resulting in the inhibition of IL-2-dependent T cell proliferation. TGF-beta-mediated suppression of T cell activation may be responsible for the prevention of effector T cell-mediated autoimmune IDDM in NOD mice by TGF-beta-producing CD4+ suppressor T cells.
MeSH terms
Acute-Phase Proteins/metabolismAnimalsCD4-Positive T-Lymphocytes/*secretionCalcium-Calmodulin-Dependent Protein Kinases/metabolismCell LineDNA-Binding Proteins/metabolismDiabetes Mellitus, Type 1/*immunology/*prevention & controlDown-Regulation/immunologyEnzyme ActivationInterleukin-2/antagonists & inhibitors/immunologyJanus Kinase 1Janus Kinase 3Lymphocyte Activation/drug effectsMiceMice, Inbred NOD*Milk ProteinsPhosphorylation/drug effectsProtein-Tyrosine Kinases/metabolismReceptors, Interleukin-2/metabolismSTAT3 Transcription FactorSTAT5 Transcription FactorT-Lymphocytes, Regulatory/*secretionTrans-Activators/metabolismTransforming Growth Factor beta/*physiology/*secretion
DOI
10.1006/jaut.1997.0137
PMID
9218758
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Endocrinology & Metabolism
AJOU Authors
윤, 지원
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