免疫学课程课件1

1、1,主 要 内 容,4、记忆性NK细胞研究,2,主 要 内 容,4、记忆性NK细胞研究,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 illuminati

2、ng 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 re

3、asonably “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 d

4、ogma 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 art

5、ifactual 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 investigator

6、s 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,The killer cel

7、ls involved would seem to be neither T nor B lymphocytes as classified by conventional markers but rather belong to yet a third group of lymphocytes,NK细胞-自然杀伤细胞,Cytolytic lymphocytes Derived from bone marrow Innate immune system: NK cell receptors are encoded in the germline and do not undergo somat

8、ic recombination like B and T cell receptors key component of the innate immune system, providing early cellular defense against viruses and intracellular pathogens, and contributing to the early detection and destruction of transformed cells,NK cell effector functions that eliminate tumor cells,Nat

9、ure 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 N

10、K 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 responsiven

11、ess,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

12、,ITAM-containing NK receptors.,Nature immunology, 2008,NK cell receptors associated with the FcRI 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, 2

13、003,type-2 transmembrane homodimer,Association of distinct NKG2D isoforms with DAP12 and DAP10,2003,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 affinitie

14、s 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, PV

15、P) 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

16、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 p

17、hosphatases 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 t

18、he 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, 2008,31,主 要 内 容,4、记忆性NK细胞研究,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-C

19、D56+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

20、 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 coordi

21、nated 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 CD

22、56 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)

23、 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 g

24、enerating 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,Wayne M. Yokoyama, M.D. Investigator, Howard Hughes Medical Institute Sam J. and Audrey Loew Levin Chair for Research on Arthritis Professor of Medicine

25、 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,Functional subsets of mouse NK cells,Immunological Reviews, 2006,CD27-CD11b+ NK cells produce more granzyme

26、 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 un

27、dergo 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,Bo

28、th 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 e