Despite much recent progress in studies of the T cell repertoire and positive and negative selection, major gaps remain. Quantitative information on the average frequency of naive T cells specific for typical antigenic peptides associated with self-MHC molecules is extremely sparse, as is the magnitude of the bias of mature T cells towards self-MHC restriction at the level of precursor cell frequencies. The nature of the repertoire before the action of positive and negative selection is completely unexplored. The relative roles of hematopoietic cells versus thymic epithelial cells in inducing positive selection is still unclear.
Our first aim i s to employ libraries of MHC binding peptides to determine the average frequency of self-MHC restricted T cells among mature CD8+ T cells, as well as the magnitude of the bias towards self-MHC restriction imposed by positive selection.
Our second aim i s to determine the nature of the primary (pre-selection) repertoire in terms of MHC-reactivity and frequency of T cells specific for MHC associated peptides.
Our third aim i s to determine the rules for T cell positive selection by hematopoietic cells versus thymic epithelial cells. While the functions of conventional CD4+ and CD8+ T cells are relatively well understood, little is known concerning a discrete population of mature T cells that expresses the NK1.1 antigen. This population includes CD4-CD8-TCRalpha-beta+ cells as well as CD4+CD8-TCRalpha-beta+ cells. Both subsets have a strongly biased T cell receptor Vbeta and Valpha repertoire and our recent data demonstrates that the selection of these cells within the thymus requires class I expression, but is independent of class II expression. The developmental relation of these cells to conventional T cells is unknown.
Our fourth aim i s to address the role of specific TCR expression in directing the production of NK1.1 + T cells versus conventional T cells.
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