: 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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049329-05
Application #
7012317
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Leitner, Wolfgang W
Project Start
2002-02-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2009-01-31
Support Year
5
Fiscal Year
2006
Total Cost
$268,294
Indirect Cost
Name
State University of New York at Buffalo
Department
Dentistry
Type
Schools of Dentistry
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260