Dietmar J. Kappes, PhD
Office Phone: 215-728-5374
Our laboratory focuses on fundamental issues in T lymphocyte development and signal transduction. To this end we have developed mouse models with specific defects of the T lymphoid lineage: 1) an induced mutant lacking the CD3δ component of the TCR signalling complex, which is blocked in positive selection of a? T lineage cells, and 2) a spontaneous mutant line carrying an autosomal recessive mutation which blocks the generation of CD4+ but not CD8+ T cells, refered to as "helper-deficient" or HD-/- mice.
The TCR is responsible for antigen-specific recognition and differential signal transduction leading to alternate cellular responses in both immature and mature T cells. For immature thymocytes alternate signals lead to either death by apoptosis (negative selection) or activation and further differentiation (positive selection). Important issues that we have examined are whether alternate responses are achieved through quantitative and/or qualitative differences in TCR-mediated signalling and whether individual components of the TCR signalling complex possess unique or redundant functions. Our work in this area has focused on the in vivo manipulation of the structure and expression of the TCR complex using unique knockout and transgenic mouse models.
T cell maturation involves key branch points at which cells choose between commitment to different lineages, i.e. β versus α T cell lineages and CD4+ helper versus CD8+ killer lineages. Commitment to the helper or killer lineages correlates precisely with the specificity (restriction) of a thymocyte's TCR towards either class I or II MHC. Although this process has been intensively studied at the phenomenological level, the intracellular pathways controlling it remain obscure. Our work in this area has focussed on the characterization of a unique line of spontaneous mutant mice, HD-/- mice, which are blocked in the generation of CD4+ helper T cells. These mice carry a specific defect in a pathway controlling lineage commitment and represent an important new tool in achieving a mechanistic understanding of this process. We are interested in the further functional characterization and genetic mapping of this interesting mutation.Description of research projects