Esther and Wendy Schekman Chair in Basic Cancer Biology, and Professor of Immunology and PathogenesisLab Homepage: http://mcb.berkeley.edu/labs2/raulet/
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 cancer cells and infected 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.
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 stimulate the cells and distinct receptors that inhibit them. We have a general aim to investigate the specificity and function of NK cell receptors, and have provided key data on many of them. NKG2D is a key activating receptor expressed by NK cells and some T cells that we are currently investigating in detail. It recognizes any of several host-encoded cell surface ligands (collectively called NKG2D ligands). NKG2D ligands are upregulated in cancer cells and cells infected with certain viruses. Engagement of a ligand on an unhealthy cell causes the NK cell to kill it and secrete cytokines. We generated knockout mice lacking the receptor and demonstrated a defect in tumor immunosurveillance, providing evidence for innate surveillance of cancer. A current emphasis in the lab is to define pathways that activate ligand expression in cancer cells and virus-infected cells. We have demonstrated the role of (a) proliferation-associated signals, specifically the E2F transcription factors, which regulate cell cycle entry but also the activate transcription of a set of NKG2D ligands in certain proliferating cell types; (b) the DNA damage response, a protein kinase cascade induced in transformed cells and certain infected cells; (c) cells exposed to heat shock; (d) the PI-3 kinase pathway (in collaboration with the Coscoy lab), activated in virus-infected cells and cancer cells. We have also found that another signal associated with cancer, specifically activation of the p53 tumor suppressor protein, promotes the recruitment of NK cells into tumors. The roles of additional pathways are under investigation. The broad aim is to dissect how these signals work together to regulate the sensitivity of unhealthy cells, and to exploit this knowledge for enhancing immunotherapy. In addition, dysregulation of this system can promote inflammatory diseases, so blockade of NKG2D has potential for therapy of such diseases.
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 unhealthy cells while preventing reactivity against self. The cellular signaling processes that underlie self tolerance of NK cells is under investigation.
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, and distinct function in the immune response. Emerging evidence indicates that different subtypes of γ/δ T cells play distinct roles in allergy, autoimmunity and host defense. We have a number of excellent tools for analyzing γ/δ T cells and we plan to investigate the specialized roles of these cells in the immune response.
We are also interested in the developmental mechanisms that generate these different sets of T cells. With the use of transgenic and gene-targeted mice, we showed that V gene promoter sequences and the location of the gene determine 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 further 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.
Iannello, A., T. W. Thompson, M. Ardolino, S. W. Lowe and D. H. Raulet. 2013. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med 210:2057-2069.
Raulet, D. H., S. Gasser, B. G. Gowen, W. Deng and H. Jung. 2013. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol 31:413-441.
Jung, H., B. Hsiung, K. Pestal, E. Procyk and D. H. Raulet. 2012. RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J Exp Med 209:2409-2422.
Vivier, E., D. H. Raulet, A. Moretta, M. A. Caligiuri, L. Zitvogel, L. L. Lanier, W. M. Yokoyama and S. Ugolini. 2011. Innate or adaptive immunity? The example of natural killer cells. Science 331:44-49.
Joncker, N. T., N. Shifrin, F. Delebecque and D. H. Raulet. 2010. Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment. J Exp Med 207:2065-2072.
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.
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.
Diefenbach, A., E. R. Jensen, A. M. Jamieson and D. H. Raulet. 2001. RAE-1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413:165-171.
Photo credit: Mark Hanson at Mark Joseph Studios.
Last Updated 2013-09-29