Antigen induced activation of human T lymphocytes leads to the de novo synthesis and secretion of interleukin-2 (IL-2) and concomitant display of high affinity lL-2 receptors. The subsequent binding of IL- 2 to these receptors initiates the poorly understood processes of subunit oligomerization and an intracellular signaling which culminate in the clonal expansion of the antigen stimulated T cells. The human lL-2 receptor is now recognized as a multimeric membrane complex composed of a least three distinct chains termed alpha (p50, Tac), beta (p70-75), and gamma-c (p64). Heteromeric assembly of these different subunits leads to surface expression of distinct forms of the IL-2 receptor displaying different ligand binding affinities and functional potentials. The beta and gamma subunits appear to play a major role in growth signaling and both are members of a new and burgeoning super-family of cytokine receptors. The highly inducible and transient nature of alpha gene expression likely plays a central role in governing the transient display of high affinity IL-2 receptors during the course of the immune response. Pathological conditions affecting the IL-2 receptor system have also been recognized. HTLV-I infection leads to the deregulated surface display of alpha subunits in the adult T cell leukemia while mutations in the gamma gene have been identified as the genetic defect underlying X- linked severe combined immunodeficiency disease (X-SCID). The current grant proposal focuses on the IL-2Rbeta chain and will explore at a molecular level both the extracellular and intracellular functions of this key cytokine receptor subunit. The first series of studies will delineate the biochemical basis for ligand binding and define the dimerization interfaces with the alpha and gamma-c subunits. Additional studies will specifically focus on the identification of functional domains within the cytoplasmic tail of beta that are essential for intracellular growth signaling and the characterization of cellular factors that bind to these specific domains. Special attention will also be given to the role of tyrosine kinase activation and tyrosine phosphorylation of IL-2Rbeta in the lL-2 growth signaling pathway. Specifically, the early induction by IL-2 of Janus tyrosine kinase family members and coupling of JAK stimulation to the activation and nuclear expression of IL-2 specific STAT factor(s) will be carefully addressed. Finally, this grant proposes to further explore the biochemical basis for HTLV-I mediated transformation of CD4+ T-cells focusing on the potential activating function of HTLV-I pl2 which may intracellularly crosslink IL-2Rbeta and gamma-c and thus trigger IL-2R signaling in the absence of IL-2. Such deregulated IL-2 receptor signaling could certainly contribute to the T cell transformation process observed with HTLV-I. In summary, these proposed studies should significantly extend our understanding of the structure and function of the human IL-2 receptor system, which in turn may permit the future design of novel pharmacological agents capable of amplifying or inhibiting IL-2 action.
| Liu, K D; Gaffen, S L; Goldsmith, M A et al. (1997) Janus kinases in interleukin-2-mediated signaling: JAK1 and JAK3 are differentially regulated by tyrosine phosphorylation. Curr Biol 7:817-26 |
| Gaffen, S L; Lai, S Y; Ha, M et al. (1996) Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity. J Biol Chem 271:21381-90 |
