The experiments described in this application are designed to investigate the mechanisms by which IL-2 enhances T cell immunity in a primary immunodeficiency disease, common variable immunodeficiency (CVI). While the phenotype of this disease is hypogammaglobulinemia, T cell defects, including defective T cell proliferation, anergy, defective CD28 co-stimulation, accelerated apoptosis, and deficient IL-2 production are characteristic of this immune defect. In recent studies we have found that the T cell defects can be reversed by the administration of IL-2, allowing an opportunity to explore some of the mechanisms by which this cytokine activates and regulates human T cell immunity. Since T cell receptor costimulation by the CD28 receptor is abnormal in CVI, a deficiency of this intracellular signaling pathway is a mechanism that could explain defective proliferation, anergy, cytokine deficiency, and premature apoptosis. Exogenous IL-2 could provide an effective by-pass of abnormal CD28 costimulation, enhancing the upregulation of the anti-apoptotic Bcl-2 proteins. We will determine in what way the CD28 signaling pathway differs from normal T cells, analyzing early signaling events, membrane reorganization, upregulation of Bcl-xL, and the effects of CD28 triggering on transcription and stabilization of cytokine mRNA. We hypothesize that a major effect of IL-2 in CVI is to prolong the survival and proliferation of antigen-activated T cells, thus we will determine if IL-2 treatment in vivo increases the numbers and/or proliferation of circulating antigen primed cells. While IL-2 rescues T cells from apoptosis, it can also prime activated T cells for Fas induced cell death, thus the effects of IL-2 treatment on Fas triggered cell death will be examined. Although IL-2 is essential for normal human immunity, and was one of the first cytokines to be used in clinical trials, IL-2 has not emerged as a clinical therapy for any condition except late stage melanoma and renal cancer. At least one reason for the lack of development of IL-2 as clinical therapeutic is that immunologic mechanisms by which IL-2 enhances and regulates human lymphoid responses in vivo are unclear. Thus, this application will focus on the cellular and molecular mechanisms by which IL-2 reconstitutes T cell immunity in this model system.
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