Interleukin 2 (IL-2) is a key growth factor for the clonal expansion of antigen activated T lymphocytes whose biological activity is mediated by binding to the high affinity IL-2 receptor (IL-2R), comprised of 3 subunits, alpha, beta and gamma. Signal transduction via the IL-2R is dependent upon the cytoplasmic tails of the beta and gamma subunits. The gamma subunit (designated gamma-c) has been recently shown to be a component of the lL-4 receptor (IL-4R) and IL-7 receptor (IL-7R), and it is highly likely a component of the IL-9R and lL-15R. Proper signal transduction from gamma-c is critical for normal lymphocyte development as mutations in the human gamma-c gene has been causally associated with X- linked severe combined immunodeficiency disease (SCID). A key issue, therefore, for understanding how not only the IL-2R but also cytokine receptors in general regulate the immune system is to establish the function of gamma-c. During the last grant period, cDNA probes and unique monoclonal antibodies (mAbs) to the IL-2Rbeta and gamma-c were generated to facilitate study of the mouse IL-2R. An in vivo system have been developed that appears to be a mouse model of X-linked SCID. By adoptive transfer of bone marrow cells and subsequent treatment of the recipient with mAbs to gamma-c, preliminary data demonstrate that gamma-c bearing cells are required for mouse T and B cell development from progenitor cells in adult bone marrow. The major objectives of this proposal are to establish the contribution of the gamma-c in T lymphocyte development and to define the physiological relevant role of cytoplasmic domains of IL-2Rbeta and gamma-c in T cell growth and differentiation into effector cells.
The specific aims are: 1) To establish the contribution of gamma-c on T and B lymphocyte development from embryonic and adult bone marrow progenitor cells; 2) to delineate whether gamma-c signalling promotes intrathymic T cell development: and 3) to determine the functional activity of lL-2Rbeta and gamma-c signal transducing modules in normal T lymphocytes. The first 2 aims will by pursued by detailed characterization of the anti-gamma-c mouse model of SCID and by production and characterization of dominant negative transgenic mice in which gamma-c signalling is inhibited in distinct cellular compartments.
For aim 3 chimeric IL-2R will be expressed in transgenic mice that are akin to producing a """"""""knockout"""""""" mouse in which discrete functional cytoplasmic domains of IL-2Rbeta or gamma-c have been mutated to test the contribution of that domain on T cell growth and differentiation into effector cells by normal T lymphocytes.
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