T cell receptor alpha and beta chain genes rearrange in immature thymocytes to provide a great clonal diversity of cells expressing receptors on their surface. Only a small fraction of these cells become mature T cells. Those expressing the most useful TCR specificities as defined by their reactivity with self major histocompatibility complex encoded molecules are selected for survival and maturation. This receptor driven process is called positive selection. Understanding the specificity of this step, and the signalling events that accompany it are the goals of this application. Fetal thymus organ culture using mice which are deficient in the recognition step of positive selection provides and in vitro system to study the recognition and signalling event in positive selection. Mice which lack beta-2 microglobulin are deficient in MHC class I surface expression and as a consequence of this do not select class I restricted, CD8+ T cells. Exogenous addition of beta-2 microglobulin plus peptides which bind class I restores this process. Positive selection is exquisitely peptide specific. Our goal is to investigate the relationship between a foreign, antigenic peptide and the selecting peptide. This will be achieved using TCR alpha-beta transgenic mice, and TCRbeta """"""""half- transgenic"""""""" mice. Identification of the physiological ligand (natural peptide) involved in the selection of thymocytes expressing certain TCR specificities is also a goal. The reactivity of T cells in the periphery to a foreign antigen is dependent on their encounter with a self-peptide 'mimic' of the antigen during the stage of positive selection in the thymus. Some instances of low- or non-responder status may map to the absence of an appropriate selecting self peptide. Future attempts to achieve T cell differentiation in vitro, or to enhance positive selection in vivo for therapy are dependent on a precise understanding of positive selection.
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