Lymphocytes employ various recognition strategies to attack viruses, microorganisms and cancer cells. The corresponding lymphocyte receptor proteins are members of diverse families, many of which are clonally distributed in expression.Our primary interests are in understanding how the various receptor molecules used by natural killer (NK) cells and T cells are employed in the recognition of pathogens and cancer cells, and how these receptors regulate lymphocyte development.
Natural killer cells. Natural killer (NK) cells play roles in immunity to viruses, parasites, and cancer cells. Individual NK cells express two classes of receptors, one that stimulates the cells, and another that inhibits. Recently, we identified a stimulatory receptor expressed by NK cells, and expression-cloned cellular ligands for this receptor. The ligands are not expressed by most normal cells, but are induced in most tumor cell lines. Expression of the ligands by tumor cells triggers a dramatic immune response resulting in tumor cell rejection. This receptor-ligand system is the first well understood stimulatory circuit in NK cells, and represents an example of a newly appreciated arm of innate immunity, in which transformed, infected, or otherwise "distressed" cells upregulate ligands that stimulate an immune attack upon the cells. Significantly, the receptor is also expressed by killer T cell. Using tumor and infection models, knockout mice and monoclonal antibodies, we are determining the role of NKG2D in immunity and investigating the signals that diseased cells to upregulate the ligands. Other stimulatory NK receptors and their ligands are under investigation.
Most inhibitory receptors expressed by NK cells recognize class I MHC molecules and function to prevent the lysis of cells that express class I molecules normally, and allow the destruction of those that do not. We have recently discovered a new inhibitory receptor-ligand interaction (NKR-P1B-Ocil) that also may play a role in recognition of diseased cells. We have uncovered fascinating cellular and molecular mechanisms that determine which inhibitory receptor genes are initially expressed by NK cells, and how these receptors influence subsequent NK cell development. The molecular basis for these mechanisms are being investigated using a combination of cellular, genetic and gene targeting approaches.
T cell development and function. In the thymus, a/b T cells and g/d T cells differentiate from a common precursor cell. We are investigating the role of cytokine signals and T cell receptor mediated signals in this process. Subsequently, in the a/b T cell lineage, selective processes allow the development of "useful" T cells from a population of early T cells with heterogeneous specificities. We demonstrated for the first time that the pre-selected T cell population is inherently reactive with polymorphic MHC molecules. Current studies investigate the germline-encoded specificity for MHC and how it is modified as T cells develop. In the g/d cell lineage, we showed that instead of a largely random gene rearrangement process, a directed V gene rearrangement process occurs, which helps to generate waves of distinct thymic progenitor cells with different specification independent of cellular selection. With the use of transgenic and gene-targeted mice, we have demonstrated that V gene promoter sequences and the location of the gene determines the order in which it is rearranged in development. The system is ideal for unraveling important features of the developmental regulation of V-D-J recombination. We recently discovered an intrathymic selection process for g/d T cells that operates in the fetal stage, and induces a gene program that enables fetal g/d T cells to migrate to intraepithelial locations. We are currently investigating the underlying molecular mechanisms.
Interested in joining our lab? Dr. Raulet can not accept graduate students directly. Please apply at UC Berkeley Graduate Division.