Immunology Graduate Program | University of California, San Francisco

We have a general interest in T lymphocyte (T cell) development and immunity. This includes, but is not limited to, an emphasis on understanding the developmental significance of interactions that occur at the T cell surface. We have ongoing projects focusing on interactions that serve either to increase or decrease the responsiveness of T cells to fate-determining cues. In some of these, we are interested in resolving basic signaling issues, whereas in others, our interest also extends to biophysical aspects of receptor-ligand interaction and the formation of productive immunological synapses.
Much of our work is founded on genetics. We use contemporary technology to manipulate the mouse genome so that we can learn more about the functions of genes that regulate the immune system.

Current areas of interest in the lab are as follows:
Determining the functions mediated by the CD4, CD5 and CD6 molecules. For CD4, we are interested in understanding how the involvement of CD4 enhances antigen recognition and potentiates both thymocyte development and TH2 differentiation. To study these issues, we have generated mice that show developmental stage-specific loss of CD4 expression and we have used these to uncover requirements for CD4 in T cell homeostasis. We are also exploiting novel in vitro systems to study signaling issues that we expect will have relevance to the regulation of Th1/Th2 differentiation. For CD5 and CD6, we have used mouse mutants and in vitro systems to show that CD5 is a negative regulator of TCR signaling and that CD6 has related, but distinct properties.

We are interested in understanding how cells move from one compartment in the thymus to another during their development. We have an ongoing project addressing the regulation of this movement by soluble/matrix associated factors and other cell surface interactions.

The functions mediated by selected members of the Tumor Necrosis Factor Receptor (TNFR) Family. We have generated and characterized mice that lack expression of the OX40 molecule (CD134) and through this work we have shown that OX40 is critical for productive T cell activation and the efficient formation of memory T cells. In ongoing work, we have generated additional mouse mutants that show absent or mutant expression of a different member of the TNFR family. The analysis of these mice is ongoing in conjunction with studies on novel cell biological mechanisms that regulate the function of this TNFR-related molecule.
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To facilitate studies such as those mentioned above, we have an ongoing interest in developing refined strategies for effecting conditional or stage-specific mutations in T cells. This has included the development of strains of mice that express the Cre recombinase at early or late stages of T cell development, or selectively during T cell activation. One off-shoot of this technological emphasis has been a collaborative effort to engineer megabas-scale chromosomal deletions in the mouse with the goal of modeling chromosomal abnormalities that are typical of human myeloid leukemia.