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1、Antigen-Presenting Cells and Antigen Presentation xiaojian Wang Institute of Immunology Zhejiang University ,Introduction Antigen-presenting cells Antigen processing and presentation,Contents,I. Antigen-presenting cell, APC,Antigen-presenting cells are required for T cell activation,A variety of cel
2、ls specialized in capturing 、processing and present the antigen to the T lymphocytes, causing either tolerance or immunity. These cells are name as Anitgen presenting cell, APC Dendritic cells, monocytes/macrophages and B cells are professional APCs.,I. Antigen-presenting cell, APC,APC染色彩图,Antigen-p
3、resenting cells,Dendritic cells,Macrophages,B cells,Non-professional APC,Endothelial cell (EC) Fibroblastic cell Activated T cell,Under some circumstances, they can express MHC II and present Ags,II. Antigen presentation,The process by which APC express peptide-MHC on their cell surface in a form re
4、cognizable by lymphocytes.,Antigen-presenting cells,I. Dendritic cells,highly branched morphology can active naive T cells markers,The Nobel Prize in Physiology or Medicine 2011,拉尔夫斯坦曼(Ralph M. Steinman)【已故】1943年出生于加拿大蒙特利尔,在麦吉尔大学学习生物学和化学。之后在美国哈佛医学院学习医学,1968年获得医学博士学位(MD)。于1970年被纽约洛克菲勒大学接纳,从1988年起成为免疫
5、学教授。担任该校免疫学与免疫性疾病中心主任。,发现树突状细胞 Dendritic cells, DC 是启动适应性免疫应答的关键细胞,R. M. Steinman and Z. A. Cohn. J. Exp. Med. 137, 11421162; 1973,1. Surface markers,MHC class I/II molecules CD1a, CD11c, CD83 (human) 33D1, NLDC145 (mouse) Co-stimulatory molecules: B7.1(CD80)/B7.2(CD86), CD40, CD44, CD54,2. Sources
6、of DC,3. Distribution and Classification of DC,DCs are found in many organs throughout the body DC in lymphoid tissue -Lymphoid tissue DC Interdigitating cell, IDC Follicular DC, FDC thymic dendritic cell, TDC DC not in lymphoid tissue-Non-lymphoid tissue DC Langerhans cells Interstitial DC DC in bo
7、dy fluid-Circulating DC Veiled cells Peripheral blood DC,Located in lymph follicles which are rich in B cells; Derived from interstitial DC; Highly express FcR, CR1 and CR2; Involved in the generation and maintenance of memory B cells.,1) Follicular DC (FDC),Follicular DC, FDC,FDC express high level
8、s of membrane receptors for antibody and complement. By these, FDC actives the B cells in lymph nodes.,2) Interdigitating DC (IDC),Main APC to induce primary immune response; Derived from Langerhans cells; FcR- and C3bR-, MHC I and IIhigh; Distributed mainly in the T cell area of secondary lymphoid
9、tissue, present Ags to T cells.,3) Langerhans cells (LC),Found in the epidermis (skin) and mucous membranes; MHC I and IIhigh, highly express FcR and C3bR, Birbeck particle (due to langerin expression); Powerful ability to capture and process Ags and migration to lymph node after activation.,Langerh
10、ans IDC,4. Development of myeloid DC,Four phases Pre-DC Monocyte, Mo Immature DC Uptake antigen Migration Mature DC Express high levels of MHC I and II, CD80, CD86, CD40, CD54, HSP, etc.,Immature DC Phenotype: high expression of receptors related to phagocytosis (FcR, CR, mannose receptor, DC-sign);
11、 low expression of CD54, CD40, CD80; CD86 and MHC II, CD14- Function: 1) strong capacity to ingest and process Ags, but weak ability to present Ags 2) induction of immune tolerance 3) sensing of infectious agents by TLR (pattern recognition receptors),Mature DC Phenotype: low expression of receptors
12、 related to phagocytosis (FcR, CR, mannose receptor); high expression of CD54, CD40, CD80, CD86 and MHC II; CD83+ and CD25+ Function: weak ability to capture and process Ags, powerful ability to present Ags.,Dendritic Cell Maturation,MHC II,5. DC in immune activation and immune tolerance,1) DC in im
13、mune activation Present antigen and activate T cells The first signal MHC II-Ag: CD4+ T cells MHC I-Ag: CD8+ T cells The second signal co-stimulating molecules cytokines IL-12,Peripheral tolerance: immature DC capture autoantigen when they migrate from non-lymphoid tissue to T cell area of secondary
14、 lymphoid tissue, and induce peripheral tolerance. Central tolerance: induced in negative selection of T cells in the thymus.,2) DC induce immune tolerance,Bone marrow,Blood,Tissue,HSC,Myeloid progenitor,Pre-monocyte,Monocyte,Monocyte,Macrophage,II Mononuclear phagocyte system (MPS) 1. Differentiati
15、on and distribution,Different names in different tissues Monocyte ( blood ) Kupffer cells ( liver ) Mesangial cells ( kidney glomerulus ) Microglia ( brain ) Alveolar macrophages ( lung ) Histiocyte ( connective tissue ),MHC-I and II molecules; CAM: LFA-1, ICAM-1, B7, CD40; FcR; CR: CR1, CR3, CR4; P
16、attern-recognition receptor (PRR): mannose receptor, scavenger receptor (CD91), Toll-like receptors,2. Surface markers,3. Biological functions of M,Antigen processing and presentation phagocytosis pinocytosis receptor-mediated endocytosis,Antimicrobial and cytotoxic activity: a number of antimicrobi
17、al and cytotoxic substances produced by activated M can destroy phagocytosed microorganisms. Reactive oxygen intermediates, nitric oxide.,Secretion of soluble factors: enzymes: lysozyme, myeloperoxidase, etc. cytokines: IL-1, IL-6, TNF, IL-12, IL-18, etc. complement: C1C9, Bf coagulation factors, PG
18、, LTs, ACTH, etc.,phagocytosis,macrophage,Ag presentation,III. B cells bone marrow-dependent lymphocyte,About 5-15% of the circulating lymphoid pool are B cells defined by the presence of surface immunoglobulin (Ig).,III. B cells,Antigen processing and presentation,Binding and uptake of antigen depe
19、nds on the physical state of the antigen and the cell type involved. Antigen processing MHC class I processing pathway MHC class II processing pathway Antigen presentation,1 Binding and uptake of antigen,Endogenous antigens: MHCI-CD8 Produced within the cells, Such as viral proteins or tumor protein
20、s processed by host cell Exogenous antigens: MHCII-CD4 Produced out of the cells, Bacteria, cells and soluble proteins processed by APC,Uptake antigen by immature DC and macrophage,Pinocytosis Liquid or small granule Phagocytosis Large molecular or microbe Receptor-mediated endocytosis effective Sel
21、ective,nonspecifically engulfed BCR-mediated,Uptake antigen by B cells,2 Antigen processing,Degradation of externally- or internally- derived antigen into short peptide sequences Association of the peptide with MHC molecules,1. The pathway of MHC I-associated endogenous Ag presentation,transported t
22、o endoplasmic reticulum by TAP,degraded by proteasome (LMP2/7) in cytoplasm,Degradation in the proteasome,The components of the proteasome include MECL-1, LMP2, LMP7.,Protein in cells including non-self proteins are degraded continuously by a multicatalytic protease of 28 subunits,Proteasome, the Cy
23、tosolic Meat Grinder That Chops Up Proteins,ENDOPLASMIC RETICULUM,CYTOSOL,Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I,LMP,TAP,Transporter-associated with antigen processing (TAP1 & 2),Transporter has preference for 8 amino acid peptides with hydr
24、ophobic C termini.,Calnexin binds to nascent class I chain until 2-M binds,2-M binds and stabilises floppy MHC,Tapasin, calreticulin, TAP 1 & 2 form a complex with the floppy MHC,Cytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compact,Maturation and loading of MHC cla
25、ss I,2. The pathway of MHC II-associated exogenous Ag presentation,Exogenous antigen newly synthesised MHC class II molecule (in the endoplasmic reticulum) endosome Ii binds in the groove of MHC class II molecule lysosome protease M II C phagolysosome li CLIP protease DM Degrade into 1215aa peptide
26、+ releasing the CLIP and allowing other peptide to bind Ag peptide/MHC class II molecule complex transport to the surface of APC, recognized by CD4+T,Phagocytosis, pinocytosis, FcR-phagocytosis BCR-receptor,Y,Pinocytosis,Phagocytosis,Membrane Ig receptor mediated uptake,Uptake of exogenous antigens,
27、Complement receptor mediated phagocytosis,Fc receptor mediated phagocytosis,opsonization,Proteases produce 24 amino acid long peptides from antigens,Exogenous pathway,Protein antigens In endosome,Cathepsin B, D and L proteases are activated by the decrease in pH,Need to prevent newly synthesised, un
28、folded self proteins from binding to immature MHC,Invariant chain stabilises MHC class II by non-covalently binding to the immature MHC class II molecule and forming a nonomeric complex,In the endoplasmic reticulum,MHC class II maturation and invariant chain,involve in the assembling and folding of
29、MHC class II molecule; Block the groove of MHC class II molecule; Lead the assembled class II molecule to M II C.,The functions of Ii:,CLIP:class II-associated invariant chain peptide,HLA-DM catalyses the removal of CLIP,MIIC compartment,HLA-DM Replaces CLIP with a peptide antigen using a catalytic
30、mechanism (i.e. efficient at sub-stoichiometric levels) Discovered using mutant cell lines that failed to present antigen HLA-DO may also play a role in peptide exchange,MIIC compartment sorts peptide-MHC complexes for surface expression or lysosomal degradation,Surface expression of MHC class II- p
31、eptide complexes,Important aspects of Ag processing,Location of pathogen dictates type of response Virus in cytosol MHC class I pathway CTL Extracellular pathogen MHC class II pathway CD4 response Ab production cytokine production,Sample question,1. Products of TAP-1 and TAP-2 genes Bind 2m. Prevent
32、 peptide binding to MHC molecules. Are part of the proteasome. Transport peptides into the endoplasmic reticulum for binding to MHC class I. Transport peptides into endoplasmic reticulum for binding to MHC class II.,Answer=D,2. Which of the following cells is professional antigen-presenting cell? -
33、( ),A. Dendritic cells B. Endothelial cells C. Neutrophils D. T cells E. Mast cells,Answer=A,3. Which of the following gene products is involved in the pathway of MHC class I associate endogenous antigen presentation? ( ),A. LMP2/7 B. Ii C. HLA-DM D. HLA-DO E. HLA-DR3,Answer=A,Review questions,What are the differences between immature DC and mature DC? Describe the pathway of MHC I-associated endogenous Ag presentation and MHC II-associated exogenous Ag presentation.,Thanks for your attention!,
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