Research is directed at investigating the cellular and genetic events that control normal T cell development. Transgenic and gene-targeting methods are used to analyze the function of known genes and various techniques (e.g.,RT-PCR, gene cloning) are being employed to identify novel genes that participate in thymocyte development. Current studies are focused on: (I) Examining the role of T cell antigen receptor (TCR) signal transduction in thymocyte maturation. In mature T cells, the TCR transduces signals important for T cell activation and cell mediated immunity. In immature T cells the TCR is required for thymocyte development and for thymic (positive and negative) selection. The TCR is composed of multiple signal transducing subunits (the CD3 chains and one or more members of the zeta-family of proteins; zeta, eta and Fcgamma) that couple the TCR to intracellular signal transduction pathways via conserved functional sequences (Immunoreceptor Tyrosine based Activation Motifs; ITAMs). To address whether these signal transducing subunits perform distinct or analogous functions in development we have: a) examined their role in T cell ontogeny by generating zeta/eta-deficient and zeta/eta/Fcgamma deficient mice by gene targeting, and then genetically reconstituting these mice with transgenes encoding the individual zeta-family proteins, and b) examined the function of the 3 individual zeta-chain ITAMs in thymocyte development and selection by transgene reconstitution of zeta-deficient mice. These studies revealed that expression of zeta chain (or a related zeta-family protein) is required for TCR surface expression but that zeta chain signals are not specifically required for T cell development. Thus the CD3 subunit ITAMs can transduce all of the signals necessary for thymocyte maturation. However, a direct relationship was observed between the number of TCR-zeta ITAMs and the efficiency of both positive and negative thymocyte selection suggesing that the multiple TCR ITAMs function primarily in signal amplification. These findings demonstrate a previously unrealized role for multiple TCR ITAMs in thymocyte selection and identify a function for signal amplification in selection of the T cell repertoire. (II) The role of other signal transducing proteins in T cell development is being examined by the generation of transgenic/knockout mice. These include the CD3 epsilon subunit of the TCR and CD5 a distinct surface receptor that also contains an ITAM-like sequence. (III) Novel genes that have potential functions in thymocyte development or T cell activation are being identified by RT-PCR. A new lymphoid-specific PTK, Txk has been cloned and biochemical and transgenic approaches are being employed to analyze its function. A similar approach has been used to identify other genes involved in early T cell development.
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