Stimulated cytokine mRNA expression in Common-Variable Immunodeficiency (CVI) patients hint at a post-transcriptional defect in cytokine secretion

Previous studies from several laboratories have shown that T cells from CVI patients secrete reduced amounts of IL2, IL4, IL10 and γ IFN when stimulated with mitogen or through the T cell antigen receptor. In order to characterize the defect in the T cells as to whether receptor signaling is dysfunctional or post-transcriptional pathways are blocked, T cells from 6 CVI patients and 4 normal controls were stimulated by a monoclonal anti-CD3 antibody (stimulation through the TcR) or PHA/PMA (bypassing the TcR). After an 18 hour incubation total RNA was isolated and different cytokine mRNAs were measured by quantitative RT-PCR. mRNA expression was measured using an internal RNA standard with primers for IL2, IL4, IL10 and γ IFN. In normal controls, after anti-CD3 stimulation, the difference between unstimulated and stimulated mRNA ranged between a 5-10 fold increase for all cytokines (50 fold for γ IFN). CVI T cells from 3/6 patients stimulated with anti-CD3 produced mRNA at levels comparable to the controls whereas the remaining 3 produced 10-200 fold more cytokine mRNA (except IL10) than the controls. Interestingly, attempts to bypass the receptor defect with PMA and PHA yielded similar mRNA data although secretion was restored. This suggests that anti-CD3 stimulated CVI T cells express a defect in cytokine mRNA transcription/translation most likely residing in the signaling pathway.