Derek Sant'Angelo, PhD

The maturation of T cells is a consequence of a series of developmental checkpoints. In an ongoing, lifelong process, immature thymocytes are rescued from programmed cell death by signals delivered by surrounding stromal cells, primarily thymic cortical epithelial cells. Remarkably, nearly all developing thymocytes die - most because of a failure of their randomly generated T cell receptors (TCRs) to appropriately interact with self-peptide:self-MHC (major histocompatibility complexes). The signals that initiate thymocyte development are collectively referred to as "positive selection". The primary focus of my laboratory is to identify, isolate and characterize thymocytes that are in the process of, or have just completed, positive selection. Genes expressed by these cells are of clear biological importance since they control the fundamental processes of survival, differentiation and maturation. Interestingly, many genes that have been identified in various carcinomas are normally only expressed during thymocyte development. Therefore, we propose that understanding the normal, regulated function of such genes may also help us to understand their aberrant function.

We also propose that positive selection genetically programs developing thymocytes for specific immunological functions. One clear and accepted example of such genetic programming is the CD4/CD8 lineage choice. Our recent work on natural killer (NK) T cells clearly demonstrates that this unusual cell type also "learns" its potent immunomodulating functions during development. We believe that distinct T cell subgroups will be found within the larger, known T cell populations (such as CD4 and CD8 T cells). By defining the developmental requirements for these cells, we believe we will be able to manipulate T cell development for therapeutic purposes by gene therapy.

Finally, we also are studying the fate of thymocytes that have failed positive selection. Thymic resident macrophages appear to be a distinct lineage that is specialized to quickly dispose of apoptotic thymocytes. Failure of apoptotic cell clearance appears to dramatically alter the function of the thymus and may lead to the escape of self-reactive T cells involved with autoimmune diseases.