The process of T-cell development depends upon both positive and negative selection to produce a population of T-cells that are reactive with foreign, but not self peptides in association with self-encoded MHC molecules. Experiments are proposed to characterize the signal transduction pathways that contribute to or determine the fate of developing thymocytes: either apoptotic death, or differentiation into CD4 or CD8 positive T-cells.
In Aim 1 experiments are proposed to determine how the MAP kinase-related molecules, Erk, JNK, and p38 affect positive and negative selection. Transgenic mice will be produced that express either constitutive or inducible forms of signaling intermediates which cause induction and nuclear translocation of one of these three serine/threonine kinases. The analysis will determine the quantitative effects on both positive and negative selection, and the differential effects on maturation into either CD4 or CD8 positive T-cells. Biochemical analyses will determine the basal level and inducible activity of the parallel Map Kinase pathways.
In Aim 2 the observation that a dominant interfering form of an atypical PKC can enhance negative selection will be investigated. The effects of this mutation on intermediates in the Ras-Erk pathway will be investigated. In addition mice with a targeted deletion in the gene encoding this molecule will be produced and the effects of this deletion on thymocyte development will be determined.
In Aim 3 the role of a calcium-calmodulin induced phosphatase, calcineurin, and kinase, CamKIIg will be investigated. Calcium-independent form of calcineurin can affect the efficiency of positive selection. the effect of this transgene on positive and negative selection, and on the activation of downstream effector molecules, such as members of the NF-AT family will be characterized. Thymic development is one of the most carefully studied models of cellular differentiation in a mammalian organism and, as such, it is important not only in understanding the function and selection of the immune system, but also as a model for cellular differentiation.
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