UNCOUPLING OF T-CELL ANTIGEN RECEPTOR AND DOWNSTREAM PROTEIN-TYROSINEKINASES IN COMMON VARIABLE IMMUNODEFICIENCY

Patients with common variable immunodeficiency (CVID) are heterogeneou s in the clinical manifestations of the disease and the underlying mec hanisms leading to the immunodeficiency. Although the overt defect is an impairment in E-cell function, there is increasing evidence of prim ary T-cell dysfunctions in a proportion of patients with CVID. We have analyzed T-cells from six CVID patients for activation of both early and late events in response to TCR triggering. The data showed that T- cells from three of six CVID patients were defective in the capacity t o initiate the TCR/CD3 signaling pathway by activating intracellular t yrosine kinases, associated with impaired proliferative responses to T CR/CD3 triggering. Since both surface expression of the TCR/CD3 comple x and intracellular expression of key tyrosine kinases such as p56lck and ZAP-70 were normal in these patients, our data suggest a defect in the earliest step of TCR signal transduction. (C) 1997 Academic Press .