David H Raulet

University of California, Berkeley, Berkeley, CA, United States

Are you David H Raulet?

Claim your profile

Publications (206)2725.53 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Various cytokines have been evaluated as potential anticancer drugs; however, most cytokine trials have shown relatively low efficacy. Here, we found that treatments with IL-12 and IL-18 or with a mutant form of IL-2 (the "superkine" called H9) provided substantial therapeutic benefit for mice specifically bearing MHC class I-deficient tumors, but these treatments were ineffective for mice with matched MHC class I+ tumors. Cytokine efficacy was linked to the reversal of the anergic state of NK cells that specifically occurred in MHC class I-deficient tumors, but not MHC class I+ tumors. NK cell anergy was accompanied by impaired early signal transduction and was locally imparted by the presence of MHC class I-deficient tumor cells, even when such cells were a minor population in a tumor mixture. These results demonstrate that MHC class I-deficient tumor cells can escape from the immune response by functionally inactivating NK cells, and suggest cytokine-based immunotherapy as a potential strategy for MHC class I-deficient tumors. These results suggest that such cytokine therapies would be optimized by stratification of patients. Moreover, our results suggest that such treatments may be highly beneficial in the context of therapies to enhance NK cell functions in cancer patients.
    Journal of Clinical Investigation 10/2014; · 13.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Natural killer (NK) cells represent a first line of defense against pathogens and tumor cells. The activation of NK cells is regulated by the integration of signals deriving from activating and inhibitory receptors expressed on their surface. However, different NK cells respond differently to the same stimulus, be it target cells or agents that crosslink activating receptors. The processes that determine the level of NK cell responsiveness have been referred to collectively as NK cell education. NK cell education plays an important role in steady state conditions, where potentially auto-reactive NK cells are rendered tolerant to the surrounding environment. According to the “tuning” concept, the responsiveness of each NK cell is quantitatively adjusted to ensure self tolerance while at the same time ensuring useful reactivity against potential threats. MHC-specific inhibitory receptors displayed by NK cells play a major role in tuning NK cell responsiveness, but recent studies indicate that signaling from activating receptors is also important, suggesting that the critical determinant is an integrated signal from both types of receptors. An important and still unresolved question is whether NK cell education involves interactions with a specific cell population in the environment. Whether hematopoietic and/or non-hematopoietic cells play a role is still under debate. Recent results demonstrated that NK cell tuning exhibits plasticity in steady state conditions, meaning that it can be re-set if the MHC environment changes. Other evidence suggests, however, that inflammatory conditions accompanying infections may favor high responsiveness, indicating that inflammatory agents can over-ride the natural tendency of NK cells to adjust to the steady state environment. These findings raise many questions such as whether viruses and tumor cells manipulate NK cell responsiveness to evade immune-recognition. As knowledge of the underlying processes grows, the possibility of modulating NK cell responsiveness for therapeutic purposes is becoming increasingly attractive, and is now under serious investigation in clinical studies.
    Seminars in Immunology 04/2014; · 6.12 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The immunoreceptor NKG2D originally identified in natural killer cells recognizes ligands that are upregulated on tumor cells. Expression of NKG2D ligands (NKG2DLs) is activated by the DNA damage response (DDR) which is often activated constitutively in cancer cells, revealing them to natural killer cells as a mechanism of immunosurveillance. Here we report that the induction of retinoic acid early transcript 1 (RAE1) ligands for NKG2D by the DDR relies on a STING-dependent DNA sensor pathway involving the effector molecules TBK1 and IRF3. Cytosolic DNA was detected in lymphoma cell lines which express RAE1 and its occurrence required activation of the DDR. Transfection of DNA into ligand-negative cells was sufficient to induce RAE1 expression. Irf3+/-;Eμ-Myc mice expressed lower levels of RAE1 on tumor cells and showed a reduced survival rate compared to Irf3+/+;Eμ-Myc mice. Taken together, our results suggest that genomic damage in tumor cells leads to activation of STING-dependent DNA sensor pathways, thereby activating RAE1 and enabling tumor immunosurveillance.
    Cancer Research 03/2014; · 9.28 Impact Factor
  • Source
    Alexandre Iannello, David H Raulet
    [Show abstract] [Hide abstract]
    ABSTRACT: We recently dissected how senescent tumors can trigger complementing signaling pathways that mobilize natural killer (NK) cells to eliminate malignant cells. In addition to cell-intrinsic effects on proliferation, senescence induces the production of chemokine (C-C motif) ligand 2 (CCL2), which recruits NK cells to mediate direct tumoricidal effects. Hence, senescence activates a cancer cell-extrinsic oncosuppression program.
    OncoImmunology 02/2014; 3(1):e27616. · 6.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, roles of the immune system in immune surveillance of cancer have been explored using a variety of approaches. The roles of the adaptive immune system have been a major emphasis, but increasing evidence supports a role for innate immune effector cells such as natural killer (NK) cells in tumor surveillance. Here, we discuss some of the evidence for roles in tumor surveillance of innate immune cells. In particular, we focus on NK cells and other immune cells that express germline-encoded receptors, often labeled NK receptors. The impact of these receptors and the cells that express them on tumor suppression is summarized. We discuss in detail some of the pathways and events in tumor cells that induce or upregulate cell-surface expression of the ligands for these receptors, and the logic of how those pathways serve to identify malignant, or potentially malignant cells. How tumors often evade tumor suppression mediated by innate killer cells is another major subject of the review. We end with a discussion on some of the implications of the various findings with respect to possible therapeutic approaches.
    Advances in Immunology 01/2014; 122:91-128. · 5.53 Impact Factor
  • Alexandre Iannello, David H Raulet
    [Show abstract] [Hide abstract]
    ABSTRACT: Pathogenic and oncogenic insults result in the induction of intrinsic defense mechanisms such as cell-death pathways and senescence, and extrinsic pathways that mobilize immune responses to destroy unhealthy cells. Both protective mechanisms presumably evolved to limit the damage these insults could inflict on the host. After viral infection or malignant transformation, unhealthy cells can be directly sensed by natural killer (NK) and some T cells via the activating receptor NKG2D. All NK cells and subsets of T cells express NKG2D. The NKG2D/ligand system represents a major recognition mechanism for detection and elimination of unhealthy cells. Here we discuss different pathways, including stress pathways, that are responsible for cell-surface display of ligands for NKG2D, which are self-proteins that are minimally expressed by normal cells. We also discuss new results indicating that efficient elimination of tumor cells that display NKG2D ligands depends on the recruitment of NK cells and other immune cells to the tumor, which can be regulated by distinct mechanisms, including the p53-dependent production of chemokines by senescent tumors. The cooperative effect of pathways that induce the display of NKG2D ligands and distinct pathways that mobilize immune cells provides a higher degree of specificity to the NK cell response.
    Cold Spring Harbor Symposia on Quantitative Biology 10/2013;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The induction of cellular senescence is an important mechanism by which p53 suppresses tumorigenesis. Using a mouse model of liver carcinoma, where cellular senescence is triggered in vivo by inducible p53 expression, we demonstrated that NK cells participate in the elimination of senescent tumors. The elimination of senescent tumor cells is dependent on NKG2D. Interestingly, p53 restoration neither increases ligand expression nor increases the sensitivity to lysis by NK cells. Instead, p53 restoration caused tumor cells to secrete various chemokines with the potential to recruit NK cells. Antibody-mediated neutralization of CCL2, but not CCL3, CCL4 or CCL5, prevented NK cell recruitment to the senescent tumors and reduced their elimination. Our findings suggest that elimination of senescent tumors by NK cells occurs as a result of the cooperation of signals associated with p53 expression or senescence, which regulate NK cell recruitment, and other signals that induce NKG2D ligand expression on tumor cells.
    Journal of Experimental Medicine 09/2013; · 13.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The NKG2D activating receptor has been implicated in numerous autoimmune diseases. We tested the role of NKG2D in models of autoimmunity and inflammation using NKG2D knockout mice and antibody blockade experiments. The severity of experimental autoimmune encephalitis (EAE) was decreased in NKG2D-deficient mice when the disease was induced with a limiting antigen dose, but unchanged with an optimal antigen dose. Surprisingly, however, NKG2D deficiency had no detectable effect in several other models, including two models of type 1 diabetes, and a model of intestinal inflammation induced by poly(I:C). NKG2D antibody blockade in normal mice also failed to inhibit disease in the NOD diabetes model or the intestinal inflammation model. Published evidence using NKG2D knockout mice demonstrated a role for NKG2D in mouse models of atherosclerosis and liver inflammation, as well as in chronic obstructive pulmonary disease. Therefore, our results suggest that NKG2D plays selective roles in inflammatory diseases.
    Clinical Immunology 09/2013; 149(3PB):432-439. · 3.77 Impact Factor
  • Source
    Assaf Marcus, David H Raulet
    Cytometry Part A 09/2013; · 3.71 Impact Factor
  • Assaf Marcus, David H Raulet
    [Show abstract] [Hide abstract]
    ABSTRACT: Natural killer (NK) cells are generally considered to be part of the innate immune system. Over the past few years, however, evidence has accumulated suggesting that NK cells have certain features that are characteristic of the adaptive immune system. NK cells reportedly respond in an antigen-specific manner to a variety of small molecules and certain viruses, and mediate enhanced responses to these antigens upon secondary exposure. In infections with mouse cytomegalovirus (MCMV), MCMV-specific NK cells undergo clonal expansion, and display increased effector function after the resolution of the infection. In addition, inflammatory conditions resulting from exposure to certain cytokines seem to promote prolonged effector function in NK cells in an antigen-non-specific fashion. Taken together, these studies reveal new aspects of NK biology, and suggest that NK cells, like T and B cells, may carry out memory responses and may also exhibit greater capacity to distinguish antigens than was previously recognized.
    Current biology: CB 09/2013; 23(17):R817-20. · 10.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The immunoreceptors NKG2D and NKp46 are known for their capacity to activate natural killer cell (NK) cytotoxicity and secretory responses in the contexts of tumors and infections, yet their roles in NK cell education remains unclear. Here, we provide the first characterization of mice deficient for both NKG2D and NKp46 receptors in order to address the relevance of their concomitant absence during NK cell development and function. Our findings reveal that NK cells develop normally in double-mutant (DKO) mice. Mice lacking NKG2D but not NKp46 showed subtle differences in the percentages of NK cells expressing inhibitory Ly49 receptors and the adhesion molecule DNAM-1. A slightly increased percentage of terminally differentiated NK cells and functional response to in vitro stimuli was observed in some experiments. These alterations were modest and did not affect NK cell function in vivo in response to MCMV infection. NKp46 deficiency alone, or in combination with NKG2D deficiency, had no effect on frequency or function of NK cells.
    Blood 05/2013; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: NK cells use NK cell receptors to be able to recognize and eliminate infected, transformed, and allogeneic cells. Human NK cells are prevented from killing autologous healthy cells by virtue of inhibitory NKRs, primarily killer cell Ig-like receptors (KIR) that bind "self" HLA class I molecules. Individual NK cells stably express a selected set of KIR, but it is currently disputed whether the fraction of NK cells expressing a particular inhibitory KIR is influenced by the presence of the corresponding HLA ligand. The extreme polymorphism of the KIR and HLA loci, with wide-ranging affinities for individual KIR and HLA allele combinations, has made this issue particularly hard to tackle. In this study, we used a transgenic mouse model to investigate the effect of HLA on KIR repertoire and function in the absence of genetic variation inside and outside the KIR locus. These H-2K(b-/-) and H-2D(b-/-) mice lacked ligands for inhibitory Ly49 receptors and were transgenic for HLA-Cw3 and a KIR B haplotype. In this reductionist system, the presence of HLA-Cw3 reduced the frequency of KIR2DL2(+) cells, as well as the surface expression levels of KIR2DL2. In addition, in the presence of HLA-Cw3, the frequency of NKG2A(+) cells and the surface expression levels of NKG2A were reduced. In line with these findings, both transgene-encoded KIR and endogenous NKG2A contributed to the rejection of cells lacking HLA-Cw3. These findings support the idea that HLA influences the human KIR repertoire.
    The Journal of Immunology 02/2013; 190(6). · 5.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mechanisms of spontaneous tumor regression have been difficult to characterize in a systematic manner due to their rare occurrence and the lack of model systems. Here we provide evidence that early-stage B cells in Eμ-myc mice are tumorigenic and sharply regress in the periphery between 41-65 days of age. Regression depended on CD4(+), CD8(+), NK1.1(+) cells and the activation of the DNA damage response, which has been shown to provide an early barrier against cancer. The DNA damage response can induce ligands that enhance immune recognition. Blockade of DNAM-1, a receptor for one such ligand, impaired tumor regression. Hence, Eμ-myc mice provide a model to study spontaneous regression and possible mechanisms of immune evasion or suppression by cancer cells.
    Blood 01/2013; · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: NKG2D is an activating receptor expressed by all NK cells and subsets of T cells. It serves as a major recognition receptor for detection and elimination of transformed and infected cells and participates in the genesis of several inflammatory diseases. The ligands for NKG2D are self-proteins that are induced by pathways that are active in certain pathophysiological states. NKG2D ligands are regulated transcriptionally, at the level of mRNA and protein stability, and by cleavage from the cell surface. In some cases, ligand induction can be attributed to pathways that are activated specifically in cancer cells or infected cells. We review the numerous pathways that have been implicated in the regulation of NKG2D ligands, discuss the pathologic states in which those pathways are likely to act, and attempt to synthesize the findings into general schemes of NKG2D ligand regulation in NK cell responses to cancer and infection. Expected final online publication date for the Annual Review of Immunology Volume 31 is March 19, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
    Annual Review of Immunology 01/2013; · 41.39 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The NKG2D stimulatory receptor expressed by natural killer cells and T cell subsets recognizes cell surface ligands that are induced on transformed and infected cells and facilitate immune rejection of tumor cells. We demonstrate that expression of retinoic acid early inducible gene 1 (RAE-1) family NKG2D ligands in cancer cell lines and proliferating normal cells is coupled directly to cell cycle regulation. Raet1 genes are directly transcriptionally activated by E2F family transcription factors, which play a central role in regulating cell cycle entry. Induction of RAE-1 occurred in primary cell cultures, embryonic brain cells in vivo, and cells in healing skin wounds and, accordingly, wound healing was delayed in mice lacking NKG2D. Transcriptional activation by E2Fs is likely coordinated with posttranscriptional regulation by other stress responses. These findings suggest that cellular proliferation, as occurs in cancer cells but also other pathological conditions, is a key signal tied to immune reactions mediated by NKG2D-bearing lymphocytes.
    Journal of Experimental Medicine 11/2012; · 13.91 Impact Factor
  • Teal Russell, Benjamin Gowen, David Raulet
    [Show abstract] [Hide abstract]
    ABSTRACT: NKG2D is an activating immune receptor found on natural killer cells, and some T-cell subsets, which binds to a family of cell surface proteins. Stressed, transformed or virally infected cells, such as cancer cells, frequently express NKG2D ligands at high levels, while normal cells show little to no expression of these ligands; therefore, a natural killer cell will destroy an abnormal cell it recognizes via the NKG2D receptor. In order to further understand the regulation of NKG2D ligand expression, we are studying the human NKG2D ligand ULBP-1. A genetic screen of a human cell line identified RNA-binding motif protein 4 (RBM4) as a potential regulator of ULBP-1; thus, our goal is to determine if RBM4, and/or RBM4 isoforms that arise as a result of alternative-splicing, are involved in ULBP-1 regulation. RBM4 is a ubiquitously expressed protein which plays a role in the alternative splicing of pre-mRNA, translation, and RNA silencing. We hypothesize that increasing RBM4 expression will also increase ULBP-1 expression. To test this hypothesis, we will over-express RBM4 or its isoforms in 293T cells via transient transfection. Our second aim is to restore RBM4 expression in a haploid human cell line in which the RBM4 gene was inactivated by insertion of a retroviral gene trap. In this case, we hypothesize that adding a functional copy of RBM4 will restore ULBP-1 expression. If we determine that RBM4 regulates ULBP-1, it is possible that RBM4 can serve as a target for cancer therapy drugs.
    2012 Society for Advancement of Hispanics/Chicanos and Native Americans in Science National Conference; 10/2012
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Infection leads to heightened activation of natural killer (NK) cells, a process that likely involves direct cell-to-cell contact, but how this occurs in vivo is poorly understood. We have used two-photon laser-scanning microscopy in conjunction with Toxoplasma gondii mouse infection models to address this question. We found that after infection, NK cells accumulated in the subcapsular region of the lymph node, where they formed low-motility contacts with collagen fibers and CD169(+) macrophages. We provide evidence that interactions with collagen regulate NK cell migration, whereas CD169(+) macrophages increase the activation state of NK cells. Interestingly, a subset of CD169(+) macrophages that coexpress the inflammatory monocyte marker Ly6C had the most potent ability to activate NK cells. Our data reveal pathways through which NK cell migration and function are regulated after infection and identify an important accessory cell population for activation of NK cell responses in lymph nodes.
    Cell Reports 07/2012; 2(1):124-35. · 7.21 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)-cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKC(KD)) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKC(KD) NK cells exhibit defective killing of MHC-I-deficient, but otherwise normal, target cells, resulting in defective rejection by NKC(KD) mice of transplants from various types of MHC-I-deficient mice. Self-MHC-I immunosurveillance by NK cells in NKC(KD) mice can be rescued by self-MHC-I-specific Ly49 transgenes. Although NKC(KD) mice display defective recognition of MHC-I-deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity-induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self-MHC-I molecules and that the absence of these receptors leads to loss of MHC-I-dependent "missing-self" immunosurveillance by NK cells.
    Blood 06/2012; 120(3):592-602. · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by peribronchial and perivascular inflammation and largely irreversible airflow obstruction. Acute disease exacerbations, due frequently to viral infections, lead to enhanced disease symptoms and contribute to long-term progression of COPD pathology. Previously, we demonstrated that NK cells from cigarette smoke (CS)-exposed mice exhibit enhanced effector functions in response to stimulating cytokines or TLR ligands. In this article, we show that the activating receptor NKG2D is a key mediator for CS-stimulated NK cell hyperresponsiveness, because CS-exposed NKG2D-deficient mice (Klrk1(-/-)) did not exhibit enhanced effector functions as assessed by cytokine responsiveness. NK cell cytotoxicity against MHC class I-deficient targets was not affected in a COPD model. However, NK cells from CS-exposed mice exhibit greater cytotoxic activity toward cells that express the NKG2D ligand RAET1ε. We also demonstrate that NKG2D-deficient mice exhibit diminished airway damage and reduced inflammation in a model of viral COPD exacerbation, which do not affect viral clearance. Furthermore, adoptive transfer of NKG2D(+) NK cells into CS-exposed, influenza-infected NKG2D-deficient mice recapitulated the phenotypes observed in CS-exposed, influenza-infected wild-type mice. Our findings indicate that NKG2D stimulation during long-term CS exposure is a central pathway in the development of NK cell hyperresponsiveness and influenza-mediated exacerbations of COPD.
    The Journal of Immunology 03/2012; 188(9):4468-75. · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The interplay between the immune system and abnormal metabolic conditions sustains and propagates a vicious feedback cycle of chronic inflammation and metabolic dysfunction that is critical for atherosclerotic progression. It is well established that abnormal metabolic conditions, such as dyslipidemia and hyperglycemia, cause various cellular stress responses that induce tissue inflammation and immune cell activation, which in turn exacerbate the metabolic dysfunction. However, molecular events linking these processes are not well understood. Tissues and organs of humans and mice with hyperglycemia and hyperlipidemia were examined for expression of ligands for NKG2D, a potent immune-activating receptor expressed by several types of immune cells, and the role of NKG2D in atherosclerosis and metabolic diseases was probed with the use of mice lacking NKG2D or by blocking NKG2D with monoclonal antibodies. NKG2D ligands were upregulated in multiple organs, particularly atherosclerotic aortas and inflamed livers. Ligand upregulation was induced in vitro by abnormal metabolites associated with metabolic dysfunctions. Using apolipoprotein E-deficient mouse models, we demonstrated that preventing NKG2D functions resulted in a dramatic reduction in plaque formation, suppressed systemic and organ inflammation mediated by multiple immune cell types, and alleviated abnormal metabolic conditions. The NKG2D/ligand interaction is a critical molecular link in the vicious cycle of chronic inflammation and metabolic dysfunction that promotes atherosclerosis and might be a useful target for therapeutic intervention in the disease.
    Circulation 11/2011; 124(25):2933-43. · 14.95 Impact Factor

Publication Stats

19k Citations
2,725.53 Total Impact Points


  • 1990–2013
    • University of California, Berkeley
      • • Department of Molecular and Cell Biology
      • • Division of Immunology and Pathogenesis
      Berkeley, CA, United States
  • 2009–2011
    • Pennsylvania State University
      • Department of Veterinary and Biomedical Sciences
      University Park, MD, United States
  • 1979–2006
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, MA, United States
  • 2002
    • University of Massachusetts Medical School
      • Department of Pathology
      Worcester, MA, United States
  • 2000
    • University of Lausanne
      • Department of Biochemistry
      Lausanne, VD, Switzerland
  • 1989
    • National Cancer Institute (USA)
      Maryland, United States
  • 1988–1989
    • Whitehead Institute for Biomedical Research
      Cambridge, Massachusetts, United States