The major goal of this proposal is to understand the role of T cell receptor/CD3 complexes (TCR complex) in which the zetu chain is missing or replaced with the FcRgamma molecule on T cell development and function. The zetu chain homodimer of conventional TCR complexes plays a major role for expression of the complexes and in TCR mediated signaling events. However, a number of CD4- negative normal T cells such as CD8alphaalpha+ gut intraepithelial lymphocytes express alternative TCR complexes containing only one or no zetu chain but a related molecule, FcRgamma. Interestingly, these T cells tend to express potentially autoreactive TCRs but they do not cause autoimmunity. The development and function of T cells expressing alternative TCR complex are unclear, but they may develop extrathymically. Alternative TCR complexes are generally expressed at lower levels than are conventional TCR complexes. In our transgenic mice in which all their T cells express alternative TCR complexes, the complexes are expressed at even lower levels on CD4+ than on CD8+ cells. Conversely, conventional TCR complexes are expressed at higher levels on CD4+ cells than on CD8+ cells in normal mice. It is hypothesized that FcRgamma evokes different downstream signaling pathways than does zetu and thus it may alter the behavior of T cells. Experiments in Specific Aim A are designed to determine the molecular and cellular mechanisms that regulate the expression level of TCR in T cells. These studies are to find out what signaling pathways are associated with alterative TCR complexes and their influences on TCR expression and function of T cells. Further experiments in Aim B will be performed to understand the role of alternative TCR complex on T cell development and function. The experiments will analyze the roles of thymus, the cytokine secretion patterns, and the influence of alternative TCR complex on T cell reactivity. Finally, Aim C is proposed to study gut associated lymphoid tissues which is not only the largest lymphoid organ but it plays a central role in mucosal immunity. We will generate TCR transgenic mice as an animal model to study the development of T cells bearing TCRs derived from the CD8alphaalpha+ gut intraepithelial lymphocytes which express alterative TCR complexes. The knowledge gained from the studies will provide important insights into the development of normal T cells bearing alternative TCR complexes and their roles in the systemic and mucosal immunity against tumors, infections, and in autoimmune diseases.
| Lee, Wen-Hui; Ramos, Thomas; Krymskaya, Ludmila et al. (2003) Development of T cells expressing an altered TCR complex. Eur J Immunol 33:2696-705 |
| Liu, C P; Jiang, K; Wu, C H et al. (2000) Detection of glutamic acid decarboxylase-activated T cells with I-Ag7 tetramers. Proc Natl Acad Sci U S A 97:14596-601 |
