Proper lymphocyte homeostasis is critical for normal immune function and is maintained by a complex series of cellular interactions and the action of secreted cytokines. The inappropriate enhancement of lymphocyte survival due to a block in programmed cell death can contribute to the abnormal expansion of clones resulting in tumorigenesis or the breakdown of peripheral self-tolerance. In addition, lack of negative immune regulation via molecular such as Fas can result in the accumulation of chronically active, but unresponsive T cells similar to cells seen in models of aging. Interleukin-4 (IL-4) is a potent survival factor for both B and T lymphocytes and has been shown to protect lymphocytes from apoptosis induced by a variety of stimuli. Our previous studies on the IL-3-dependent myeloid progenitor cell type 32D and normal B lymphocytes found a role for Insulin Receptor Substrate (IRS) family members and their recruitment of PI-3' kinase in signaling the IL-4 induced prevention of programmed cell death initiated by factor withdrawal. Treatment with IL-4 will also protect B and T cells from apoptosis induced by agents such as BCR and TCR stimulation and Fas/FasL stimulation. There is no information on the mechanism by which IL-4 mediates this protection. Therefore, our broad goal is to understand the molecular mechanisms of IL-4 mediated regulation of receptor-induced apoptosis. We propose that stimulation of the IRS pathway will protect lymphocytes from apoptosis induced by death-promoting signals.
The specific aims designed to test this hypothesis are as follows. 1) We will delineate the contribution of the IRS pathway to the IL-4-induced protection of T lymphocyte tumor lines and normal T cells from death. 2) We will characterize the signaling pathways activated by IL-4 in B cell tumors that mediate protection from death induced by anti-IgM and anti-Fas. 3) We will determine the sites of IL-4 action on the downstream pro-apoptotic cascade activated by these receptor (ie. caspases). Completion of these aims will delineate the mechanisms of protection from anti-IgM and anti-Fas induced death by IL-4 and further our understanding of the balance between life and death in the immune system.
