MOLECULAR ROLE OF TGF-BETA, SECRETED FROM A NEW-TYPE OF CD4(-CELL, NY4.2, IN THE PREVENTION OF AUTOIMMUNE IDDM IN NOD MICE() SUPPRESSOR T)

A new type of CD4(+) T cell clone (NY4.2) isolated from pancreatic isl et-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 tha t the cytokine TGF-beta, secreted, from the cells of this clone, is th e substance which prevents autoimmune IDDM. This investigation was ini tiated to determine the molecular role TGF-beta plays in the preventio n 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, in hibits IL-2-dependent T cell proliferation in HT-2 cells (IL-2-depende nt T cell line) and NOD splenocytes. We found that TGF-beta suppresses IL-2-dependent T cell proliferation. Second, we determined whether TG F-beta inhibits the activation of Janus kinases (JAKs), as well as sig nal transducers and activators of transcription (STAT) proteins, invol ved in an IL-2-induced signalling pathway that normally leads to the p roliferation of T cells. We found that TGP-beta inhibited tyrosine pho sphorylation of JAK1, JAK3, STAT3 and STATS in Con A blasts from NOD s plenocytes and HT-2 cells. Third, we examined whether TGF-beta inhibit s the cooperation between STAT proteins and mitogen-activated protein kinase (MAPK), especially extracellular signal-regulated kinase 2 (ERK 2). We found that TGF-beta inhibited the association of STAT3 and STAT S with ERK2 in Con A blasts from NOD splenocytes and HT-2 cells. On th e 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 i n T cells from NOD splenocytes, resulting in the inhibition of IL-2-de pendent T cell proliferation. TGF-beta-mediated suppression of T cell activation may be responsible for the prevention of effector T cell-me diated autoimmune IDDM in NOD mice by TGF-beta-producing CD4(+) suppre ssor T cells. (C) 1997 Academic Press Limited.