Mark M. Davis

Research/Lab website:   http://cmgm.stanford.edu/hhmi/mdavis

We are interested in the molecular basis of T and B lymphocyte recognition, as well as the control of differentiation and functional responses in these cells. In particular, we have studied the biochemical basis of T cell receptor binding to antigen/MHC complexes and find that the strength of the interactions is a very good predictor of what the resulting T cell response will be. We also find that T cell receptor-peptide/ MHC complexes have an inherent ability to form oligomers and that this could be part of the ‘trigger’ for T cell activation. One spin-off of these biochemical studies has been the development of tetrameric peptide/MHC reagents which have proven to be generally useful for staining and characterizing antigen-specific T cells in complex mixtures of lymphocytes (i.e. McMichael and Callaghan, J. Exp. Med., 187:1367-1371, 1998). Among other things, we have used these tetramers to follow tumor specific T cells in patients with Melanoma and other cancers. In one patient where we see a substantial number of CD8+ T cells specific for a tumor antigen, the cells have no cytolytic activity and thus seem to have been ‘anergized’ by the tumor. We are now working with a number of groups that have developed different vaccination strategies to determine which strategies are best able to produce a useful response.

Another important aspect of T cell recognition that is something of a ‘black box’ is the mystery of what actually happens on the surface of T cell while it is surveying an antigen presenting cell. To investigate this we have made a large series of green fluorescent protein tagged cell surface molecules, expressed them in B or T lymphocytes and followed their movements using multi-color video microscopy. Thus far we find that many key molecules (ICAM-1, CD48, class II, MHC) on the B cell cluster to the interface with a T cell within seconds after the first rise in internal calcium (in the T cell) and the corresponding movement of complimentary membrane molecules on the T cell may be a key factor in the phenomenon of co-stimulation. That is, the augmentation of T cell responses that is characteristic of responses triggered in T cells when B cells, dendritic cells, or macrophages are the antigen presenting cells. Some of these videos can be seen at http://cmgm.stanford.edu/hhmi/mdavis.

Another area of interest is the structural basis of T cell receptor or antibody binding to their respective antigen/MHC or antigenic ligands. For some years we have noted the extreme sequence diversity in the V(D)-J regions of T cell receptors (the CDR3 loops) and proposed that these sequences are primarily responsible for peptide recognition. Recent X-ray structural analysis and other studies support this contention and suggest that the equivalent diverse CDR3 loops in immunoglobulins also play a key role in specificity determination.