| Christopher Allen
We have demonstrated that B cells that switch to the IgE isotype differ from B cells that express other isotypes such as IgG1. We are identifying the signals mediated by the IgE B cell receptor that regulate cell fate.
Other Research in Dr. Allen's Lab
Allergy and Asthma • Immune Regulation • Inflammation
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Using our transgenic model of primary HBV infection, we established that that non-classical NKT cells that are CD1d-restricted, but non-reactive to a-GalCer, mediate the acute liver injury in our transgenic mouse model of acute hepatitis B virus infection. We now demonstrate a role for NKG2D and its ligands in this non-classical NKT cell-mediated immune response to Hepatitis B virus, and the subsequent acute hepatitis that ensues. Current experiments focus on understanding the role of NKG2D and its ligands in activation of non-classical NKT cells and NK cells; and on understanding HBV-dependent modulation of NKG2D and its ligands.
Other Research in Dr. Baron's Lab
HIV and Viral Immunity • Inflammation
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Our efforts to modulate T cell activation have centered on understanding and altering the positive signals delivered by the antigen-specific T cell receptor and secondary, so-called co-stimulatory signals, or engaging the negative regulatory events such as CTLA-4 and Notch that control T cell signal transduction. The studies focus on the yin/yang of the CD28/CTLA-4 pathways which are essential for a homeostatic T cell response. We have used soluble receptor antagonists, monoclonal antibodies and animals deficient in individual members of the CD28/CTLA-4/B7 pathways to define their individual roles in autoimmunity. In addition, we are interested in the negative regulation of immunity focused on the role of PD-1/PD-L1 pathways in the control of tissue specific tolerance. Moreover, this work has led to the examination of a number of other co-stimulatory molecules (4-1BB, PD-1, ICOS and CD40L) in the development and progression of diabetes and transplantation. We have begun to elucidate the biochemical basis of this regulatory signal through the interaction of these molecules with the TCR complex. We hope that the insights gained from these studies will help in the development of a new generation of tolerogenic drugs that will "turn off" selected parts of the immune system, leaving the disease-fighting capabilities intact.
Other Research in Dr. Bluestone's Lab
Diabetes and Autoimmunity • Immune Regulation
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Work in the Brodsky laboratory focuses on the intracellular transport and signaling of immune receptors on B cells, T cells and natural killer cells. Current projects include defining the role of clathrin at the immunological synapse, how immune receptor signaling regulates receptor internalization and how receptor expression on natural killer cells is controlled by membrane traffic.
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The Cyster lab studies how signaling from antigen and pattern-recognition receptors alters the response of lymphocytes and dendritic cells to guidance cues such as chemokines and sphingosine-1-phosphate (S1P).
Other Research in Dr. Cyster's Lab
Diabetes and Autoimmunity • Development and Differentiation • Immune Regulation • Immune Response to Microbial Pathogenesis
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IL-13 and IL-4 are major participants in allergic and asthmatic responses. We are studying the mechanisms by which these cytokines regulate gene expression and cellular function in lung cell, especially airway epithelial cells. These studies could lead to the development of new strategies for treating asthma.
Other Research in Dr. Erle's lab:
Allergy and Asthma
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A core focus of our laboratory is the immunological synapse-the junction between T cells and their stimulating APCs. We have interest in the role of the actomyosin cytoskeleton in driving T cell receptors along the cell surface and into microclusters. Additionally, we are investigating the role of polarity regulators in modulating T cell reactivity.
Other Research in Dr. Krummel's lab
Autoimmunity • Immune Regulation • Tumor Immunology
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NK cells express activating and inhibitory receptors that regulate their immune responses against virus-infected cells and tumors (hyperlink to Lanier, Annu Rev Immunol. 2005;23:225-74.) We have identified two signaling adapter proteins, named DAP12 and DAP10, that associate with several distinct NK receptors and are responsible for initiation of cellular activation. The DAP12 adapter protein contains an immunoreceptor tyrosine-based activation motif (ITAM), which recruits the Syk and ZAP70 tyrosine kinases (hyperlink to Lanier et al. Nature. 1998 Feb 12;391(6668):703-7.) DAP12 provides signaling activity for the human activating KIR molecules, the mouse activating Ly49 receptors, and several myeloid cell receptors, including MDL-1, and the TREM family of receptors. Recently, we have shown that DAP12 is involved in not only activating immune responses, but may also negatively regulate activation mediated by the Toll-like receptors (hyperlink to Hamerman et al. Nat Immunol. 2005 Jun;6(6):579-86). DAP10 is another signaling adapter, expressed by NK cells, T cells and myeloid cells, which recruits the p85 subunit of PI3-kinase and activates the AKT pathway (hyperlink to Wu et al. Science. 1999 Jul 30;285(5428):730-2.) DAP10 associated with the NKG2D receptor, which has been implicated in immunity against virus-infected cells, tumors, and autoimmunity. Our lab focuses on the structure and function of these NK receptors and their signaling pathways in innate and adapter immunity.
Other Research in Dr. Lanier's Lab
HIV and Viral Immunity • Diabetes and Autoimmunity • Tumor Immunology
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The lab works with a number of mutant mouse strains that have defects in tyrosine kinase based signaling mechanisms. These include mutants in Src-family and Syk tryrosine kinases, as well as strains lacking downstream signaling molecules. These enzymes participate in a number of signaling reactions, including cytokine, chemokine, Fc receptor, Toll-like receptor and integrin signal transduction pathways. We are using the mutant mice to help dissect these intracellular pathways, with a primary focus on signaling in innate immune cells (neutrophils, macrophages, and dendritic cells.)
Other Research in Dr. Lowell's Lab
Diabetes and Autoimmunity • Inflammation
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Our work on intracellular mechanisms of coordinating signal transduction events has focused on the molecule A20. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine that stimulates multiple cellular activation and survival signaling pathways. By targeting the TNF induced A20 gene, we found that A20 deficient mice develop profound autoimmunity coupled with an inability of A20 deficient cells to terminate TNF induced NF-kB responses (Lee et al, Science 2000). We subsequently generated A20 TNF and A20 TNFR double mutant mice, and found that A20 is critical for regulating toll-like receptor (TLR) induced NFkB signals that commit both innate and adaptive immune responses (Boone et al, Nature Immunology 2004). Moreover, we have found that A20 is also critical for terminating JNK signals. Thus, A20 mediates cross-talk between NFkB and JNK signaling pathways. Moreover, we have found that A20 is a unique ubiquitin modifying enzyme that requlates both the activity and stability of signaling proteins Wertz et al, Nature 2004; Boone et al, Nature Immunology 2004). A20 is thus a biochemically unique molecule that is critical fro regulating multiple signaling pathways and biological processes that depend on these pathways. Recent studies indicate A20 is expressed in T cells and dendritic cells, and may play critical roles in regulating both innate and adaptive immune responses. Ongoing studies focus on the physiological targets of A20’s enzymatic activity, the biochemical mechanisms by which A20 functions, the regulation of A20 activity, and the roles of A20 in regulating T cell and dendritic cell activation and survival.
Other Research in Dr. Ma's Lab
Immune Regulation • Immune Response to Microbial Pathogens • Inflammation • Diabetes and Autoimmunity
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Jennifer Puck, MD, came to UCSF in 2006 as Professor of Pediatrics in the Division of Immunology and Rheumatology and Associate Program Director for Pediatrics in the CTSI Clinical Research Center. Dr. Puck¹s research is in human primary immunodeficiencies. Her scientific contributions include mapping and identification of the genes for X-linked severe combined immunodeficiency (XSCID) and autoimmune lymphoproliferative syndrome (ALPS); a clinical trial of retroviral gene therapy for patients with XSCID who failed bone marrow transplantation; and definition of the disease and gene defects in STAT3 in hyper-IgE syndrome, or Job's syndrome, a multisystem disorder. On the translational side, she has developed a test to screen all newborns for severe lymphocyte disorders and is planning a large pilot trial. Dr. Puck also uses mouse models to probe lymphocyte development and is investigating a new gene identified by her lab that when knocked out results in arrest of T cell development from common lymphoid presursors.
Other Research in Dr. Puck's Lab
Diabetes and Autoimmunity • Development and Differentiation
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Our lab studies how lymphocytes make "yes versus no" decisions (immune responses) and how the controlled nature of this process can be lost (autoimmune disease or leukemia/lymphoma). We study these processes at the level of Ras activation, which is a sensitive signaling switch that is strongly triggered after antigen receptor stimulation. In addition, we investigate how Ras activation in the basal state regulates gene expression programs.
We strive to unravel the details of regulated and deregulated Ras activation using cell lines, mathematical models, mouse models, and patient samples.
Other Research in Dr. Roose's Lab
Development and Differentiation
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This is a major interest in our laboratory. We have focused on receptors that activate or inactive tyrosine kinases in cells of the innate immune system, including NK cells and macrophages. As a separate effort, Dr. Seaman directs a laboratory within the Alliance for Cellular Signaling (http://www.signaling-gateway.org/) a consortium of laboratories that collaborates in the study of cell signaling with a particular focus on G-protein coupled receptors.
Other Research in Dr. Seaman's lab:
Allergy and Asthma • Tumor Immunology • Diabetes and Autoimmunity
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H. capsulatum survives and replicates in the phagosome or phagolysosome of macrophages. How this fungus colonizes an intracellular niche that is normally hostile to microbes is a mystery. The ability of H. capsulatum to prevent acidification and maturation of the phagosome is thought to play an important role in survival in macrophages. We hypothesize that H. capsulatum produces gene products that block phagosome maturation and acidification. One of our main research goals is to use molecular genetic approaches to uncover which pathogen molecules are required to inhibit phagosome maturation. We are also using functional genomics to decipher which host genes are manipulated by the pathogen. We are part of a program project grant to study the immune response to intracellular pathogens, so this work is informed and influenced by studies of the interaction of host cells with Listeria monocytogenes, Mycobacterium tuberculosis, and Francisella tularensis in the in the laboratories of Dan Portnoy (UC Berkeley), Jeff Cox (UCSF), and Denise Monack (Stanford), respectively. A comparative analysis of approaches employed by these four intracellular pathogens will allow us to contrast strategies employed by a diversity of microbes.
Other Research in Dr. Sil's lab:
Immune Response to Microbial Pathogens
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B-lymphocytes as mutator mutants
Whether they lead to cancer, aging, or both, somatic mutations are usually detrimental to the individual. Mutations at the immunoglobulin (Ig) loci are an exception, because they generate high-affinity antibodies, which are important in memory responses to pathogens. Thus, in the segments of immunoglobulin genes that encode the V regions of antibodies, mutations are beneficial. Since such mutations arise at a rate a million times higher than the normal, spontane-ous mutation rate at other loci, the process is called hypermutation. With our experiments we define cis and trans-acting elements for hypermutation at the immunoglobulin loci.
But hypermutation is not the only change mature B lymphocytes undergo. Small, resting B lymphocytes all start out producing IgM antibodies. Upon encountering antigen, the cells become activated and make a switch from IgM to other immunoglobulin classes. This class switch serves to distribute a particular variable region to different Ig constant regions. Each constant region mediates a specialized effector function and so through switching an organism can guide its antibodies to various sites. Creating the new heavy chain requires loop out and deletion of DNA between switch regions. These DNA acrobatics require transcription of the switch regions, presumably so that necessary factors can gain access to the DNA. These requisite switching factors include the cytidine deaminase AID and components of general DNA repair, including mismatch repair, and double strand break repair. Yet many important factors remain to be discovered, especially those that may guide recombination to a particular subclass, and these are the factors we concentrate on.
Other Research in Dr. Wabl's lab:
Development and Differentiation • Tumor Immunology • Inflammation
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We’d like to have a clear understanding of how critical kinases and phosphatases are turned on and off during an immune responses. We are using artificial inhibitors, structural biology and structure function studies to approach this problem.
Other Research in Dr. Weiss's Lab
Diabetes and Autoimmunity • Development and Differentiation
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