The focus is on T cell development with implications for generation of distinct T cell lineages as well as acute lymphoblastic T cell leukemia (T-ALL). T cell receptor transgenic mice have been utilized to elucidate mechanisms of positive selection that result in the generation of CD8+ killer cells, CD4+ helper cells and CD4+ regulatory cells that express Foxp3. Presently, research focuses on T cell receptor and TGF-beta signaling pathways that permit conversion of nae T cells into regulatory T cells in vivo and result in antigen-specific tolerance to transplantation antigens. In disease models it was determined that antigen-specific Tregs can suppress tumor-specific immune response by preventing exocytosis of cytolytic granules by CD8 T cells during the effector phase.
Experiments concerned with T cell receptor- and Notch-signaling have revealed that lineage commitment is instructed by the intensity of TCR signals and that Notch signaling is mandatory for the generation of alpha/beta but not gamma/delta lineage cells. Overexpression of intracellular Notch results in T-ALL with highly reproducible phenotypes making it feasible to determine the contribution of oncogenes, tumor suppressors, genomic instability and microRNAs to molecular pathways of malignancy.