T cell signaling and autoimmune diabetes.

Stimulation of the T-cell lymphocyte surface receptor (TCR) initiates a cascade of intracellular signaling events leading to proliferation, anergy, cytokine secretion, or apoptosis. In prediabetic NOD mice, T cell proliferative hyporesponsiveness has been correlated to decreased TCR-mediated signal transduction along the PKC/p21ras/p42mapk pathway. Limited data regarding T cell signaling defects are available in patients with autoimmune diabetes mellitus. Some but not all investigators have found decreased in vitro proliferative hyporesponsiveness to lectin mitogens or anti-CD3 mAb associated with impaired PKC activation and cytokine production. More recently, defective expression and function of the p21ras cascade was reported in these patients. Taken together, these data suggest that lymphocytes from animals and patients with autoimmune diabetes have defective TCR mediated signaling which may result in aberrant T cell activation and proliferation. This may lead to an imbalance of Th1/Th2 cytokine secretory pattern and thereby promote disease development.