Of all the lymphocytes bearing antigen receptors, T cells are the least understood. This disparity stems from the fact that T cells were discovered by the cloning of the TCR and - genes and not by their functional properties. Since their discovery over two decades ago, we have learned that T cells recognize a different set of antigens than T cells and play unique roles in immunity, as evidenced by their ability to mediate wound healing and tumor surveillance. However, despite these advances in the area of T cell biology, the structure and signaling properties of the T cell antigen receptor (TCR) remain poorly understood. Recently, we performed a detailed analysis of the subunit composition and signaling potential of the TCR on ex vivo T cells. We found: (1) a striking difference in the subunit composition of the signal-transducing complexes of the - and TCRs, in that TCRs, unlike TCRs, lack CD3 dimers and (2) signal transduction by the TCR to be more robust than that of the TCR after CD3 crosslinking as measured by calcium mobilization, ERK activation and cellular proliferation. This unexpected difference in - and TCR signaling potential has resulted in a revision in our understanding of T cell development and function. In this research proposal, we hypothesize that the observed differences in - and TCR signal transduction are due to differences in the intracellular signaling pathways coupled to the - and TCRs. To investigate this, we employed global gene expression profiling to identify signaling molecules that are differentially expressed in mature and T cell populations. Unexpectedly, we found that B lymphoid kinase (Blk), a Src family protein tyrosine kinase (PTK) normally expressed in B lineage cells, is expressed in T cells but not in T cells. The goal of this research proposal is to determine the biological significance of Blk expression in T cells. Specifically, we will 1) characterize the expression pattern, subcellular localization, and activity of Blk in lineage cells and 2) analyze commitment, development and effector function of lineage cells in blk-/- mice. The proposed study will increase our knowledge of the processes that specifically govern the development and function of T cells. In addition, the results from this investigation will provide a foundation for future studies aimed at testing whether this qualitative difference in the expression of Src PTK family members in and T cells contributes to the enhanced signaling proficiency of the TCR. Public Health Relevance: It is expected that this study will provide important information about T cells. This knowledge will aid in the design of vaccines aimed at improving resistance to tumor cells and pathogens by specifically targeting T cells.
It is expected that this study will provide important information about T cells. This knowledge will aid in the design of vaccines aimed at improving resistance to tumor cells and pathogens by specifically targeting T cells.
|Samuelson, Elizabeth M; Laird, Renee M; Maue, Alexander C et al. (2012) Blk haploinsufficiency impairs the development, but enhances the functional responses, of MZ B cells. Immunol Cell Biol 90:620-9|
|Hayes, Sandra M; Laird, Renee M (2012) Genetic requirements for the development and differentiation of interleukin-17-producing ?? T cells. Crit Rev Immunol 32:81-95|
|Laird, Renee M; Laky, Karen; Hayes, Sandra M (2010) Unexpected role for the B cell-specific Src family kinase B lymphoid kinase in the development of IL-17-producing ?? T cells. J Immunol 185:6518-27|