The human IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. The current focus is on mechanisms of signal transduction. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ralpha, IL-2Rbeta, and gammac. Dr. Leonard cloned IL-2Ralpha in 1984, his group discovered IL-2Rbeta in 1986, and reported in 1993 that mutation of the gammac chain results in X-linked severe combined immunodeficiency (XSCID) in humans and in 1995 that mutations of the gammac -associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID. The group is now evaluating the basis for T-NK+ SCID. Although Jak3 primarily associates with gammac, it can also associate with IL-2Rbeta. The mechanism by which Jak3 can associate with IL-2R? has been further clarified. To identify other signaling molecules recruited by gammac, the yeast two-hybrid system has been used to identify interacting proteins. One of these is calpain, a calcium-activated protease that can cleave gammac following T-cell activation and therefore can serve to potentially regulate gammac-mediated signaling. gammac -deficient mice were previously generated as a model of human XSCID. Studies are now underway to try to use these as animal targets towards gene therapy for XSCID. These mice exhibit an age-dependent expansion of peripheral CD4+ T cells. Interestingly, the group reported that these mice exhibit both accelerated proliferation and accelerated apoptosis, but given the net expansion, it is clear that the degree of apoptosis is insufficient. These studies further provided data that the gammac plays a vital role in regulating lymphoid homeostasis. Additional IL-2 signaling pathways, including the basis for PI 3-kinase activation, have been studied and clarified. Efforts to clarify the basis for negative regulation of the IL-2Ralpha system are also in progress. Finally, the group reported the cDNA cloning of a receptor component of the human IL-4 and IL-13 receptors and demonstrated that, analogous to gammac, that it was located on chromosome X. Overall, these studies clarify signaling pathways in normal T-cells, in SCID, and enhance our understanding of cellular transformation.
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