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Research Interests

The regulation of T cell differentiation is not only a fascinating topic in developmental biology but is central to an understanding of how immune responses are generated. The major goal of our work is to elucidate mechanisms controlling cell fate decisions in developing T cells. We are especially interested in the role of the T cell antigen receptor (TCR) and how it works together with other developmental cues to specify cell fate. Precursor T cells undergo a testing process in the thymus to ensure that cells expressing useless or self-reactive receptors do not mature (positive and negative selection). Both of these selection processes require TCR engagement of self MHC antigens, but the precise nature of these interactions determine whether the cells will live or die. Thymocytes also receive signals as they mature that direct them into specific lineages. Precursor T cells first must specify the ab or gd T cell fate. Those that develop in the ab pathway must choose whether to become CD4 helper or CD8 cytotoxic T cells. Our studies demonstrate that the type of TCR (ab versus gd) in the first decision, and MHC class I or class II recognition by TCRab and the CD8 or CD4 coreceptor in the second, are able to generate quantitatively distinct signals that impose a bias on cell fate. Signals through the transmembrane receptor Notch and other receptors also play a role in these decisions. We would like to understand how these various receptor signals are regulated in thymocytes and how they are integrated in the process of lineage commitment.

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