David Raulet

Dept Co-Chair & C.H. Li Chair of Immunology & Pathogenesis Professor of Immunology and Pathogenesis

Lab Homepage: http://mcb.berkeley.edu/labs2/raulet/

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Research Interests

Lymphocytes employ various recognition strategies to attack viruses, microorganisms and cancer cells. Our primary interest is in understanding how natural killer (NK) cells and T cells recognize and destroy diseased cells, how their recognition apparatus is coordinated with differentiation of immune cells, and how this information can be used for therapy or prevention of disease. 

Current Projects

Natural killer cells, NKG2D and NK self tolerance. Natural killer (NK) cells play roles in immunity to viruses, parasites, and cancer cells. Individual NK cells express receptors that stimulates the cells and distinct receptors that inhibit them. We identified NKG2D as a stimulatory receptor expressed by NK cells and some T cells, which plays a role in tumor immunosurveillance and resistance to viral infections, and cloned cellular ligands for this receptor. The ligands are not expressed by most normal cells, but are induced in tumor cells and certain infected cells. Expression of the ligands by tumor cells triggers a dramatic immune response resulting in tumor cell rejection. We generated knockout mice lacking the receptor and demonstrated a defect in tumor immunosurveillance, presenting important evidence for innate surveillance of cancer. This receptor-ligand system  represents an example of a newly appreciated arm of innate immunity, in which transformed or infected cells increase expression of cell surface ligands that stimulate an immune attack upon the cells. We are uncovering principle mechanisms that activate ligand expression in cancer cells and virus-infected cells. These include stress responses associated with disease and cancer, such as an active DNA damage response and a heat shock response, and other mechanisms that couple excessive cellular proliferation to ligand expression. The various stress and proliferative signals act at different stages of ligand biogenesis, and we propose they together represent a "bar code" that signifies the diseased status of the cell. We are investigating the role of NKG2D in both NK cells and T cells in protective responses against cancer and viruses, and also in pathologic responses such as in chronic inflammatory responses and autoimmunity. 

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. Although NK cells are considered components of the innate immune response, we discovered that they have the potential to attack self cells, and this potential must be limited by mechanisms that render NK cells self-tolerant. The self-tolerance mechanism represents a tuning mechanism that sets the triggering threshold of individual NK cells so as to maximize reactivity against diseased cells while preventing NK autoreactivity. The cellular signaling process that underlies self tolerance of NK cells is under investigation. In a related project, we are investigating the function of another inhibitory receptor, NKR-P1B, whose ligand (Clrb) we discovered, specifically determining the role of a hammerhead ribozyme in the Clrb mRNA in the regulation of Clrb expression.  

T cell development and function. α/β T cells and γ/δ T cells differentiate in the thymus. In the γ/δ cell lineage, we showed that instead of a largely random gene rearrangement process, as occurs in the α/β lineage, a directed V gene rearrangement process occurs, which helps to generate waves of distinct thymic progenitor cells with different specificities 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 molecular regulation of V-D-J recombination during development. We discovered an intrathymic selection process for γ/δ T cells that operates in the fetal stage, and induces a gene program that enables fetal γ/δ T cells to migrate to intraepithelial locations. Using gene knockout mice, we have also discovered a new disease susceptibility that results from a deficiency of γ/δ T cells. 

Selected Publications

Nice, T. J., L. Coscoy and D. H. Raulet. 2009. Posttranslational regulation of the NKG2D ligand Mult1 in response to cell stress. J Exp Med 206:287-298.

Joncker, N. T., N. C. Fernandez, E. Treiner, E. Vivier and D. H. Raulet. 2009. NK cell responsiveness is tuned commensurate with the number of inhibitory receptors for self-MHC class I: the rheostat model. J Immunol 182:4572-4580.

Raulet, D. H. and N. Guerra. 2009. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol 9:568-580.

Guerra, N., Y. X. Tan, N. T. Joncker, A. Choy, F. Gallardo, N. Xiong, S. Knoblaugh, D. Cado, N. R. Greenberg and D. H. Raulet. 2008. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28:571-580.

Raulet, D. H. and R. E. Vance. 2006. Self-tolerance of natural killer cells. Nat Rev Immunol 6:520-531.

Fernandez, N. C., E. Treiner, R. E. Vance, A. M. Jamieson, S. Lemieux and D. H. Raulet. 2005. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood 105:4416-4423.

Gasser, S., S. Orsulic, E. J. Brown and D. H. Raulet. 2005. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436:1186-1190.

Xiong, N., C. Kang and D. H. Raulet. 2004. Positive selection of dendritic epidermal gammadelta T cell precursors in the fetal thymus determines expression of skin-homing receptors. Immunity 21:121-131.

Raulet, D. H. 2003. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3:781-790.

Diefenbach, A., E. R. Jensen, A. M. Jamieson and D. H. Raulet. 2001. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413:165-171.

Last Updated 2010-08-11