Immunodeficiency patients whose low levels of expression of the T cell receptor for antigen was caused by genetic defects resulting either in a CD3-gamma/- or a CD3-epsilon(low) phenotype have been described recently. Although we detected such genetic defects only in isolated cases, incomplete or altered TCR/CD3 complexes may frequently play a paramount role in a variety of inherited and acquired immunodeficiencies. Dysfunctional T cell receptor/CD3 complexes trigger only some of the available multiple signal transduction cascades. Our in vitro biochemical studies lead to the conclusion that different segments of the cytoplasmic tails of CD3-epsilon and -zeta interacted with and recruited distinct signal transduction molecules. These observations combined with the results of studies with transgenic mice provided evidence for the hypothesis that the different segments of the CD-epsilon and -zeta polypeptide chains played a distinct role during intra-thymic development, but are functionally redundant during antigen driven activation of mature T cells. Simply put: The CD3-epsilon transduction module plays a major role in very early thymocyte development, i.e. prior to the CD3-CD4-/8- stage, whilst the three zeta elements """"""""kick in"""""""" at the CD4+/8+ stage. Further in vivo studies of altered TCR/CD3 complexes(i.e. in patients and animal models) are necessary for our precise understanding of the role CD3-epsilon and -zeta in thymic differentiation. Here we propose to examine the role of the CD3-epsilon and -zeta signal transduction elements in novel immunodeficient transgenic mouse strains with blocks in T cell development. We believe that this approach is warranted as we have already generated transgenic immunodeficient T cell- /NK cell- (CD3-epsilon(H)+/+), zeta-/- mice and because we have discovered a novel dysfunctional Fc(epsilon)R(gamma) expressing T cell in the murine intestinal epithelium.
The Specific Aims of this proposal are to: 1. Further analyze the effect of CD3-epsilon over-expression on pre-thymocyte development. 2. Examine the role of CD3-epsilon in thymic differentiation in mice which lack the CD3-epsilon gene. 3. Study the impact of the zeta and Fc(epsilon)R1(gamma) signal transduction motifs on T cell development in CD3-zeta-/- mice. 4. Define the requirements for selective induction of Fc(epsilon)Rg expressing T cells by screening for the appearance of TCR/CD3(high) T cells in zeta-/- mice.
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