The consequences of the positive and negative selection process have finally been clearly defined, most notably using TCR-transgenic mice and monoclonal antibodies that identify distinct TCR. Also, consensus has been reached with respect to the order of events during initiation of TCR gene transcription and rearrangements and appearance of the most critical T cell surface proteins during fetal thymocyte development. Yet, many questions remain to be answered, and those that are the subject of the most active areas of research include those regarding selection and commitment:

1. What is the molecular nature of the signals leading to clonal deletion of immature thymocytes, and how are these different from signals leading to activation of mature T cells?

2. What is the nature of the signals involved in selection of the T cell repertoire that dictate the difference between positive and negative selection?

3. What is the nature of the signals leading to initiation and termination of TCR gene rearrangements?

Clearly, future research will be focused on identification of components of signaling pathways and regulatory molecules, and identification of lineage determining genes. These studies will no doubt reveal connections to developmental biology in other systems, a prediction illustrated nicely by the 'winged helix' class of gene regulators, which determine cell fate in Drosophila, while regulating development of the thymic stroma in mice.

See also: CD3; CD4; CD8; Clonal deletion; Cytokines; Thymic epithelium: potential role in regulatory T cell tolerance; Ontogeny of the immune response; Super-antigens; T cell receptor, ap; T cell receptor, 78; Thymus; T lymphocyte activation; T lymphocyte clonal expansion; T lymphocytes; Tolerance, peripheral.

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