Thymic T-cell development is a complex process which requires the expansion and commitment of pluripotent precursor cells to the T lineage, rearrangement and expression of the T-cell receptor (TCR), positive/negative selection, and maturation of functional immunoreactive T lymphocytes. Cytokines, especially those dependent upon the common gamma chain (gammac) of the interleukin (IL)-2 receptor (IL-2R), play pivotal roles at multiple points in T-cell developmental scheme. IL-7Ralpha and IL-2Rbeta, mostly likely as a component of the IL-15R, function early at the pro-pre-T cell level to regulate survival and growth as well as subsequent differentiation into NK cells and TCR gamma/delta+ cells. Their most recent work provides compelling data that IL-2Rbeta, most likely as a component of the IL-2R, regulates the production of self-reactive T-cells within the thymus. The molecular basis by which these cytokine receptors regulate the developmental pathways is largely unexplored. This application contains two major objectives. The goal is to more precisely define the signal transduction pathways emanating from IL-2Rbeta and IL-7Ralpha that are responsible for the survival and expansion of pro/pre-T cells, the differentiation TCR gamma/delta+ cells, and the regulation of self-reactivity. As there is considerable overlap in known signal transduction pathways between the IL-2R and IL-7R, this analysis will include an assessment of the extent by which a given thymic developmental process is dependent upon a common signaling pathway. The second major objective is to ascertain the cellular basis by which the IL-2R normally prevents self-reactivity. The development of unique cytokine receptor transgenic mice will facilitate the proposed studies.
The specific aims are: 1) To characterize the role of IL-7Ralpha and IL-2Rbeta cytoplasmic subdomains that function in growth, death, and differentiation during thymic development. 2) To investigate the interrelationship for ligand binding and subsequent signaling between IL-2R/IL-15R and IL-7R for the production, maintenance, and selection/differentiation of thymocytes. 3) To distinguish whether thymic IL-2Rbeta controls autoimmunity at the level of positive/negative selection or by promoting the differentiation of a critical regulatory T-cell subset.
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