免疫学课程1.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,主 要 内 容,4,、记忆性,NK,细胞研究,1,Natural Killer cells:Artifact to reality,The“discovery”of a new phenomenon in science is often the result of an accumulation of information with a gradual recognition that something new is being observed.,Less often is a discovery of a sudden illuminating event in the mind of a single investigator.,Often the discovery of a new phenomenon occurs while investigating a known phenomenon.Rather than having made the new observation in the context of a search for new phenomena,the investigator may make an innovative observation while investigating a reasonably“well defined”area of science.,So it was for the discovery of natural killer cells in the early 1970s,Robert K.Oldham,1983,The phenomenon of cell-mediated immunity or reactivity as measured by cellular cytotoxicity assays was reasonably“well defined”in the early 1970s,The immunologic dogma at that time stated that tumor-related,cell-mediated,cytotoxic reactions were due to tumor-associated antigens to which T lymphocytes had become previously sensitized,Occasional normal individuals showed reactivity against tumor cell lines in vitro,but this reactivity was often felt to be artifactual or due to technical problems in the assay.It was apparent by 1972 that several difficulties with these assays needed attention,the need was apparent for a conference to define some of the problems in cellular cytotoxicity assays.Such a conference was held Jun 8-9,1972,and investigators in the field cellular cytotoxicity were invited to present their results and to discuss the technical aspects of their assay systems.,By 1973 it was clear that NK activity was a phenomenon seen in several species,including mice,rats,and man,The phenomenon of Natural cytotoxicity,NK cell effector functions that eliminate tumor cells,Nature Reviews Cancer,2002,Nomariski optics visualization of the“blebbing effect”of the NK cell damage to the P815 cancer cell membranes,JIBTVA,2012,SEM normal villous surface of the P815 cancer cell,The killing of the P815 cell by NK cell,JIBTVA,2012,TEM sequence of events showing a presumptive NK cell approaching the cancer cell,The killing of the cancer cell by the injection of the toxin with resulting“blebbing”of the cancer cell membrane,JIBTVA,2012,Lewis L.Lanier,Ann.Rev.Immunol,2005,NK cell responses to targets:“Missing-self”revisited,The rheostat concept of NK cell responsiveness,Nature reviews/Immunology,2012,NK cell receptors,Activating receptors,Inhibitory receptors,Activating NK cell receptors,ITAM(immunoreceptor tyrosine-based activation motifs)-bearing NK receptor complexes,NKG2D receptor complexes,NK receptor signaling not involving ITAM-based or DAP10 pathways,ITAM-containing NK receptors.,Nature immunology,2008,NK cell receptors associated with the Fc,RI,and CD3,adaptor proteins.,2003,NK cell receptors associated with DAP12,2003,ITAM-mediated signaling in NK cells,Nature immunology,2008,The NKG2D gene and the NKG2D receptor,Nature reviews/Immunology,2003,type-2 transmembrane homodimer,Association of distinct NKG2D isoforms with DAP12 and DAP10,2003,University of California,Berkeley,David Raulet,Nature immunology,2008,DAP10-mediated signaling in NK cells,NKG2D ligands,Annu.Rev.Immunol.2005.,The diverse nature of NKG2D ligands,Nature reviews/Immunology,2003,Domain structures and affinities of various NKG2D ligands,Nature reviews/Immunology,2003,NK receptor signaling not involving ITAM-based or DAP10 pathways,CD160,:activating NK cell receptor recognizes contain HLA class I molecules,DNAM-1,:also called CD226,expressed by human NK cells,CD112(also known as polio virus receptor,PVP)and CD155(also called nectin-2)are ligands for DNAM-1.Indicated in NK cell migration and cellular activation,CD244:,also called 2B4,CD244 receptor complexes in NK cells,Activating NK cell receptors,Nature immunology,2008,Inhibitory NK cell receptors,Most of the inhibitory receptors engage MHC I molecules expressed by target cells,All of the inhibitory KIRs(killer cell immunoglobulin-like receptors)and Ly49 receptors possess ITIM(immunoreceptor tyrosine-based inhibition motisf)in their cytoplamic domains,Upon engaging a MHC class I ligand,these ITIMs are phosphorylated and recruit phosphatases to counteract cellular activation.The predominant phosphatases associated with KIR and Ly49 are Src homology(SH)-containing tyrosine phosphatase(SHP)-1 and SHP-2,Both mice and humans also express a CD94/NKG2A heterodimeric receptor that recognizes a complex of a peptide derived from the class Ia leader sequence presented by a specific nonclassical MHC I molecule(HLA-E in humans and Qa-1 in mice),Structure and function of KIR,Blood Reviews,2006,Inhibitory NK receptors,Nature immunology,2008,主 要 内 容,4,、记忆性,NK,细胞研究,30,NK,细胞发育分化,人,NK,细胞发育分化,小鼠,NK,细胞发育分化,人,NK,细胞发育分化,Human NK cells are CD3,-,CD56,+,NKp46,+,Blood,2008,Human NK cell subsets,Blood Reviews,2006,NK cells develop from BM-derived HSCs through a common lymphoid progenitor(CLP)capable of giving rise to all lymphocyte subsets,The acquisition of the interleukin(IL)-15 receptor(IL-15R),chain(CD122)marks an important step in NK cell differentiation downstream of the CLP,Bone marrow is acknowledged as a primary site for NK cell development,recently studies indicate that NK cells may develop via a local process of differentiation within various tissues,including the thymus,lymph node(LN)and intestine.,A series of coordinated differentiation and maturation steps of NK cell development,Proposed model of in vivo human NK cell development,Immunological Reviews,2006,Representative analysis by flow cytometry demonstrating the progression of NK cell development within human SLT,Immunological Reviews,2006,Progressive CD56 expression by in vivo stages of human NK cell differentiation,JEM,2006,Schematic representation of human NK cell development and terminal differentiation,Frontiers in Immunology,2013,Peripheral NK cell subsets,Cytometry Part A,2013,Human IL-15 responsive CD34,+,NK cell precursors(stage 2 cells)are naturally relatively enriched in secondary lymphoid tissues,Seminars in Immunology,2014,Morphology and immunophenotypes of the stages of human NK cell maturation in secondary lymphoid tissues,Seminars in Immunology,2014,Extramedullary human natural killer(NK)cell development as a means of generating functionally distinct and tissue-specific NK cells,2013,Multiple sites for NK-cell development,Nature Reviews/Immunology,2007,小鼠,NK,细胞发育分化,spleen,LN,LN,Wayne M.Yokoyama,M.D.,Investigator,Howard Hughes Medical Institute,Sam J.and Audrey Loew Levin Chair for Research on Arthritis,Professor of Medicine and of Pathology and Immunology,Washington University School of Medicine in St.Louis,Schematic representation of the cellular intermediates of mouse natural killer(NK)cell development,2013,LN,spleen,Functional subsets of mouse NK cells,Immunological Reviews,2006,CD27,-,CD11b,+,NK cells produce more granzyme B upon viral infection,Plos Pathogens,2008,NK cell subsets in different organs,Chemoattractant receptor expression during mouse NK cell development and transcription factors involved in NK cell commitment and maturation,Frontiers in Immunology,2014,NK cell education during development,NK cells undergo an education process during development where by cells that are potentially self-reactive are rendered anergic,MHC class I molecules play a critical role in NK cell education,there is considerable debate regarding the types of cell interactions(or lack thereof)that influence this process,Both inhibitory and activating receptors play role in NK cell education,Both hematopoietic and non-hematopoietic cells may play a role,Models of NK cell education,Disarming Model,:High responsiveness is the default state for NK cells,but encounters with normal cells that lack ligands for inhibitory receptors drives the cells into a hyporesponsive state(“disarms”them),Arming Model,:When inhibitory receptors on NK cells engage MHC I molecules on neighboring normal cells a higher state of responsiveness is induced.When thisinteraction is impossible,NK cells persist in a hyporesponsive state,which is often characterized as an immature state.The arming concept to be essentially equivalent to the“licensing”concept of NK cell education,which suggests that encounters with MHC I license the maturation of NK cells.,Tuning model,:,It proposes that each NK cell,depending on the inhibitory(and stimulatory)receptors expressed,and the MHC genotype of the animal,receives a varying amount of stimulation and inhibition when encountering neighboring cells.Stimulatory and inhibitory signals are thought to be integrated by the NK cell.The model proposes further that depending on the net stimulation received,the NK cell assumes a quantitatively appropriate responsiveness state.,Functional plasticity of NK cells,-Education and re-education of NK cells,2010,