Home Faculty and Research Faculty by Name David Raulet

David Raulet

Professor of Immunology and Pathogenesis

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

Full Directory Information

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. 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 some T cells, and 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  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. Recently, we have uncovered a principle mechanism that induces ligand expression in cancer cells: the DNA damage response pathway, which detects DNA damage in cells and either repairs the damage or induces cell death. Genomic abnormalities in tumors are known to induce the DNA damage response, providing a means for the immune system to detect cancerous cells.  Significantly, the NKG2D receptor also enhances responses by killer T cells. Using tumor and infection models, knockout mice and monoclonal antibodies, we are determining the role of NKG2D in immunity.

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 novel process that leads to self-tolerance of NK cells that would otherwise attack normal cells. The cellular signaling process that underlies self tolerance of NK cells is under investigation. We have also discovered a new inhibitory receptor-ligand interaction (NKR-P1B-Ocil) that regulates NK cell activation. 

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 developmental regulation of V-D-J recombination. We recently 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. Finally, using gene knockout mice, we have discovered a new disease susceptibility that results from a deficiency of γ/δ T cells. 

Selected Publications

Self-tolerance of natural killer cells. [D. H. Raulet, R. E. Vance (2006) Nat Rev Immunol 6, 520-531]

The DNA damage response arouses the immune system. [S. Gasser, D. H. Raulet (2006) Cancer Res 66, 3959-3962]

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

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

Positive selection of dendritic epideral γδ T cells precursors in the fetal thymus determines expression of skin-homing receptors. [N. Xiong, C. Kang, and D. H. Raulet (2004) Immunity 21, 121-131]

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

The genomic arrangement of T cell receptor variable genes is a determinant of the developmental rearrangement pattern. [N. Xiong, J. E. Baker, C. Kang, and D. H. Raulet (2004a) Proc Natl Acad Sci USA 101, 260-265]

Missing self-recognition of Ocil/Clr-b by inhibitory NKR-P1 natural killer cell receptors. [J. R. Carlyle, A. M. Jamieson, S. Gasser, C. S. Clingan, H. Arase, and D. H. Raulet (2004) Proc Natl Acad Sci USA 101, 3527-3532]

Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. [A. Diefenbach, E. Tomasello, M. Lucas, A. M. Jamieson, J. K. Hsia, E. Vivier, and D. H. Raulet (2002) Nature Immunol 3, 1142-1149]

The role of the NKG2D immunoreceptor in immune cell activation and natural killing. [A. Jamieson, A. Diefenbach, C. McMahon, N. Xiong, J. R. Carlyle, and D. H. Raulet (2002) Immunity 17, 19-29]

Redundant and unique roles of two enhancer elements in the TCRγ locus in gene regulation and γδ T cell development. [N. Xiong, C. Kang, and D. H. Raulet (2002) Immunity 16, 453-463]

Rael and H60 ligands of the NKG2D receptor stimulate tumor immunity. [A. Diefenbach, E. R. Jensen, A. M. Jamieson, and D. H. Raulet (2001) Nature 413, 165-171]

Evidence that gammadelta versus alphabeta T cell fate determination is initiated independently of T cell receptor signaling. [J. Kang, A. Volkmann, and D. H. Raulet (2001) J Exp Med 193, 689-698]

Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. [A. Diefenbach, A. M. Jamieson, S. D. Liu, N. Shastri, and D. H. Raulet (2000) Nature Immunol. 1, 119-126]

The MHC reactivity of the T cell repertoire prior to positive and negative selection. [J. Zerrahn, W. Held, and D. H. Raulet (1997) Cell 88, 627-636]

Last Updated 2006-10-31