SEVERE COMBINED IMMUNODEFICIENCY DUE TO DEFECTIVE BINDING OF THE NUCLEAR FACTOR OF ACTIVATED T-CELLS IN T-LYMPHOCYTES OF 2 MALE SIBLINGS

Peripheral blood lymphocytes (PBL) and alloreactive T cell lines of tw o male infants born to consanguinous parents and presenting with sever e combined immunodeficiency (SCID) showed a pronounced deficiency in T cell activation. Although phenotypically normal, the proliferative re sponse of the childrens' T cells was strongly reduced but could be imp roved by the addition of interleukin-2 (IL-2). Furthermore both childr ens' T cells were unable to produce the cytokines IL-2, interferon-gam ma (IFN-gamma), IL-4 and tumor necrosis factor-alpha (TNF-alpha). This multiple cytokine production deficiency could not be restored by IL-2 or co-stimulatory signals provided by antigen-presenting cells (APC). Moreover, mRNA for IL-2 and IFN-gamma could not be detected. In contr ast, expression of the activation-dependent cell surface markers CD25 and CD69 was within normal limits. To determine whether the functional defect of the patients' T cells was due to the absence or abnormal bi nding of transcription factors involved in cytokine gene expression, e lectrophoretic mobility shift assays were used to examine the DNA bind ing of AP-1, Oct, CREB, SP1, NF-kappa B and the nuclear factor of acti vated T cells (NF-AT) to their respective response elements in the pro moter of the IL-2 gene. Whereas AP-1, NF-kappa B, Oct, CREB and SP1 di splayed normal binding activities in nuclear extracts, the binding of NF-AT to its IL-2 promoter response element was barely detectable both before and after T cell stimulation. Our results strongly suggest tha t this NF-AT/DNA binding defect is responsible for the multiple cytoki ne deficiency and the SCID phenotype observed in the two infant brothe rs.