Specific deficiency of p56(lck) expression in T lymphocytes from type 1 diabetic patients

Peripheral T lymphocyte activation in response to TCR/CD3 stimulation is re duced in type 1 diabetic patients. To explore the basis of this deficiency, a comprehensive analysis of the signal transduction pathway downstream of the TCR/CD3 complex was performed for a cohort of patients (n = 38), The ma in result of the study shows that T cell hyporesponsiveness Is positively c orrelated with a reduced amount of p56(lck) in resting T lymphocytes. Upon CD3-mediated activation, this defect leads to a hypophosphorylation of the CD3 zeta -chain and few other polypeptides without affecting the recruitmen t of ZAP70. Other downstream effecters of the TCR/CD3 transduction machiner y, such as phosphatidylinositol 3-kinase p85 alpha, p59(fyn), linker for ac tivation of T cells (LAT), and phospholipase C-gamma1, are not affected. In some patients, the severity of this phenotypic deficit could be linked to low levels of p56(lck) mRNA and resulted in the failure to efficiently indu ce the expression of the CD69 early activation marker. We propose that a pr imary deficiency in human type 1 diabetes is a defect in TCR/CD3-mediated T cell activation due to the abnormal expression of the p56(lck) tyrosine ki nase.