: The mammalian immune system is regulated by soluble proteins termed cytokines. In particular, the cytokines interleukin (IL)-2 and IL-15 play central roles to regulate activation and homeostasis of T cells, as well as to direct development of several important lineages of immune effector cells. IL-2 and IL-15 are used in a number of clinical settings to treat cancer and HIV and many immunosuppressant drugs center around IL-2 production or function. Moreover, genetic deficiencies in certain cytokine receptor components cause several immunodeficiency and/or autoimmune syndromes. Understanding how the receptors for these cytokines function in a normal individual is likely to have direct bearing on treating the many diseases that involve cytokine activity. The signaling portion of the IL-2 receptor (IL-2R) is composed of two subunits, IL-2RB and gamma-c. Both are also used by the IL15R, so these cytokines elicit very similar responses in target cells. Strikingly, gamma-c is also employed by three other cytokine receptors, and consequently, a genetic deficiency in gamma-c causes X-linked severe combined immunodeficiency. The goal of this project is to explore mechanisms by which the IL-2 and IL-I5 receptors deliver specific signals in vitro and in vivo with a focus on the specific contributions of gamma-c. The IL-2Rbeta chain appears to be the workhorse of signal transduction, in that the majority of IL-2- and IL-15-induced signaling events are initiated by direct physical association of signaling molecules with phosphorylated tyrosines located on its cytoplasmic tail. Despite the fact that gamma-c is also phosphorylated on tyrosine following receptor stimulation, very few specific pathways have been directly linked to this chain, and none through its tyrosines. However, this application demonstrates that gamma-c-derived signals are involved in protecting T cells from apoptosis induced by cytokine deprivation, which is a major biological function of IL-2. Specifically, a severely truncated form of IL-2Rbeta (Beta- deltaABC, which lacks all cytoplasmic tyrosines) paired with gamma-c can still promote survival of a T cells in culture, but fails to provide protection when paired with a tyrosine-deficient form of gamma-c. Preliminary evidence indicates that this pathway involves a member of the phosphatidylinositol 3'-kinase family member and results in upregulation of the anti-apoptotic mediator Bcl-2. The long term goal of this research is to define the molecular mechanisms and biological significance of the signals that derive primarily from gamma-c by studying signaling in the context of the truncated IL-2Rbeta-deltaABC chain. First, this research will define the specific molecular regions within the gamma-c required for anti-apoptotic signaling (Aim 1). Second, this work will identify signaling intermediates in the anti-apoptotic signaling cascade by isolating and characterizing proteins that associate with gamma-c (Aim 2). Third, experiments are proposed to determine the functional significance of this anti-apoptotic signaling in vivo by creating transgenic mice that express the IL-2Rbeta-deltaABC deletion, and assessing consequences to the immune system (Aim 3).
| Gaffen, S L; Hajishengallis, G (2008) A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. J Dent Res 87:817-28 |
| Shen, Fang; Gaffen, Sarah L (2008) Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine 41:92-104 |
