Dr. Raulet, a recognized expert in NK cells and tumor immunology, who has collaborated on studies to differentiate mouse NK cells from ES cells, will adapt the human culture system to promote the differentiation of human NK cells and gdT cells. Success in developing the culture system will enable detailed dissections of cellular interactions, genetic regulatory events, and DNA rearrangements that underlie T and NK cell development.
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. Raulet 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. He has 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, Raulet's lab 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.
Raulet's laboratory has defined several mechanisms whereby NK cells become inactivated in tumors and approaches to reverse the inactivation to restore the anti-tumor response. His efforts today focus on developing novel anti-cancer therapies that mobilze the NK response against cancer.
In the News
UC Berkeley cancer immunologists are teaming up with colleagues working on infectious disease to create a new Immunotherapeutics and Vaccine Research Initiative.