医学免疫学课件：8 APC and Ag presentation 2014

1、IMMUNOLOGY,Antigen-Presenting Cells and Antigen Presentation,chapter,Outline:,What are APC and professional APC? Describe MHC class I and MHC class II presentation pathways. What are the physiological significances for these two pathway The difference between immature Dendritic Cell and mature DC. W

2、hat is Cross presentation? What the function of CD1 molecule?,Introduction Antigen-presenting cells Antigen processing and presentation MHC I-associated endogenous Ag presentation pathway MHC II-associated exogenous Ag presentation pathway Cross presentation CD1 presentation pathway,Contents,Introdu

3、ction Antigen-presenting cells Antigen processing and presentation MHC I-associated endogenous Ag presentation pathway MHC II-associated exogenous Ag presentation pathway Cross presentation CD1 presentation pathway,Contents,A variety of cell types which can take up, process antigen and carry antigen

4、 in a form (antigenic peptide-MHC molecule complex) that can stimulate lymphocytes. Dendritic cells, monocytes/macrophages and B cells are professional APCs.,Antigen-presenting cell, APC,The category of APC,Cells that express MHC class I, present endogenous antigen Are killed by CD8+ cells Are calle

5、d Target cells Cells that express MHC class II, present exogenous antigen Activate the CD4+ T cell response Are called Antigen presenting cells,Professional APCs Dendritic cells, macrophages and B cells, which can express MHC class II molecules. Non-professional APC Endothelial cell (EC) Fibroblasti

6、c cell Activated T cell,Under some circumstances, they can express MHC II and present Antigen,Antigen presenting cells,APC染色彩图,Antigen-presenting cells,Dendritic cells,Macrophages,B cells,The characteristics of APCs,Antigen presentation,The process by which certain cells in the body (APC) express an

7、tigen peptide-MHC molecule complex on their cell surface in a form recognizable by T lymphocytes.,Antigen-presenting cells,树突状细胞（Dendritic cell, DC）,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

8、, CD54,Dendritic cells (DC),2. Sources of DC,HSC,Myeloid progenitor,Lymphoid progenitor,Myeloid DC,Mo,macrophage,Myeloid DC,PMN,Lymphoid DC,3. Classification of DC,Conventional dendritic cell (cDC) or Myeloid DCs (mDC): secrete IL-12 and be a major stimulator of T cells. Plasmacytoid dendritic cell

9、(pDC) or Lymphoid DCs (LDC): can produce high amounts of IFN-, exert anti-virus effect.,Conventional DCs,Lymphoid tissue DC follicular DC (FDC), interdigitating DC (IDC), thymic DC Non-lymphoid tissue DC Langerhans cell, interstitial DC Circulating DC peripheral blood DC, veiled cell,1) Interdigitat

10、ing DC (IDC),Derived from Langerhans cells; FcR- and C3bR-, MHC I and IIhigh; Distribute mainly in the T cell area of secondary lymphoid tissue. Present Ags to T cells Main APC to induce primary immune response.,Interdigitating DC( IDC ）,Express high level of class, MHC molecules and B7，lack of FcR

11、and CR, can stimulate T cells.,Main APC to induce secondary immune response; Derived from interstitial DC; MHC -, highly express FcR, C3bR; Locate in lymph follicles which are rich in B cells; involved in the generation and maintenance of memory B cells.,2) Follicular DC (FDC),3) Langerhans cells (L

12、C),Immature DC 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.,4. Development of myeloid DC,(1) DC precursors Mo

13、nocytes are the common precursor of macrophage and DC,Phenotype: high expression of PRRs (Toll-like recptors, mannose receptor), FcR and CR; low expression of MHC II and co-stimulatory molecule Cellular organlle: MHC calsscompartment, lysosome, Endosome Cytokine: Chemokine and proinflammatory CK suc

14、h as IL-1, IL-6, IL-12, TNF- secreted by LC Function: Powerful ability to capture and process Ags, but weak ability to stimulate T cells (or weak ability to present Ags); induction of immune tolerance .,(2) Immature DC,(3) Mature DC Phenotype: low expression of PRRs (Toll-like recptors, mannose rece

15、ptor), FcR and CR; high expression of MHC I/II and co-stimulatory molecule (CD54/ICAM-1 , CD40, CD80, CD86 ); CD1a and CD83+. Function: weak ability to capture and process Ags, powerful ability to present Ags.,Difference between iDC and mDC,5. The function of DC,1) Capture and process antigen, parti

16、cipate innate immunity The expression of receptors related to phagocytosis (FcR, CR, Toll-like receptor, mannose receptor); pDC produce high amounts of IFN-, exert anti-virus effect.,5. The function of DC,2) DC in immune activation Present antigen and activate T cells The first signal MHC II-Ag: CD4

17、+ T cells MHC I-Ag: CD8+ T cells The second signal co-stimulating molecules cytokines: IL-12,3) Immune regulation secrete CKs and chemokines. 4) Induce immune tolerance,Central tolerance: induced by negative selection of T cells in the thymus. Peripheral tolerance: immature DC capture autoantigen wh

18、en they migrate from non-lymphoid tissue to T cell area of secondary lymphoid tissue, and induce peripheral tolerance.,The Nobel Prize in Physiology or Medicine 2011,Ralph M. Steinman,Dendritic cells, DC,R. M. Steinman and Z. A. Cohn.J. Exp. Med. 137, 11421162; 1973,How T cell find the right dendrit

19、ic cell,Nature. 2004 427(6970):154-9,Short T cell-DC contacts during phase I,T cell(green) Antigen-loaded DC(red),Stable Tcell-DC interaction during phase II,T cell(green) Antigen-loaded DC(red),Antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation

20、,Nat Immunol. 2008 ;9(3):282-91,P14 T cell(green) C-peptide-loaded DC(red) OT-1 (blue),Bone marrow,Blood,Tissue,HSC,Myeloid progenitor,Pre-monocyte,Monocyte,Monocyte,Macrophage,II. Monocytes and macrophages 1. Differentiation and distribution,Different names in different tissues Monocyte ( blood ) K

21、upffer 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; CKR: M-CSFR; FcR; CR: CR1, CR3, CR4; Pattern-recognition receptor (PRR): mannose receptor, scavenger r

22、eceptor, Toll-like receptor,2. Surface markers,The process of M activation,3. Biological functions of M,(1) Phagocytosis and cytotoxic activity : a number of antimicrobial and cytotoxic substances produced by activated M can destroy phagocytosed microorganisms. Reactive oxygen intermediates, NO, pro

23、teinases. (2) Antigen processing and presentation,phagocytosis,Opsonization,(3) Secretion of soluble factors to regulate immune response enzymes: lysozyme, myeloperoxidase, etc. cytokines: IL-1, IL-6, TNF, IL-12, IL-18, etc. complement: C1C9, Bf coagulation factor, PG, LTs, ACTH, etc.,(4)Immune regu

24、lation: Up-regulation: Ag-presentation; secretion of cytokines that up-regulate immune response,e.g.IL-12,IL-18 Down-regulation: inhibitory M produce IL-10, TGF-, PG, etc.,III. B cells,BCR-mediated phagocytosis enrich antigen when antigen concentration is low.,Markers of B cells,Downloaded from: Stu

25、dentConsult (on 1 June 2006 03:50 PM), 2005 Elsevier,Mechanisms of Th cell-mediated activation of B cells,B cell-mediated immune response,The edge of lymphoid follicle,Introduction Antigen-presenting cells Antigen processing and presentation,Contents,Antigen presentation,The process by which certain

26、 cells in the body (APC) express antigen peptide-MHC molecule complex on their cell surface in a form recognizable by T lymphocytes.,I. Uptake of antigens,exogenous antigens Bacteria, cells and soluble proteins processed by APC endogenous antigens Produced within the cells, Such as viral proteins or

27、 tumor proteins processed by host cell,Y,The site of pathogen replication or mechanism of antigen uptake determines the antigen processing pathway used,Cytosolic compartment Endogenous processing (Viral antigens, tumor antigens),Vesicular Compartment Contiguous with extracellular fluid Exogenous pro

28、cessing (Streptococcal, Mycobacterial antigens),Distinct mechanisms of antigen generation are used to raise T cells suited to the elimination of endogenous or exogenous pathogens,INTRACELLULAR REPLICATION,EXTRACELLULAR OR ENDOSOMAL REPLICATION,1. Uptake of Ag by DC,phagocytosis Macropinocytosis Rece

29、ptor-mediated endocytosis,2. Uptake of Ag by macrophages,Phagocytosis Pinocytosis Receptor-mediated endocytosis,3. Uptake of Ag by B cells,Pinocytosis BCR-mediated endocytosis,II. Ag processing and presentation,Two Antigen Processing Pathways,Endogenous antigens in cytosol presented on class I MHC m

30、olecules to CD8+ T cells. Exogenous antigens in endosomes presented on Class II MHC molecules to CD4+ T cells.,1. The pathway of MHC I-associated endogenous Ag presentation,endogenous antigen (such as virus Ag, tumor Ag) antigen peptide（8-13 aa） Peptide/MHC-I molecule complex to surface of APC submi

31、t to CD8+T,transported to endoplasmic reticulum by TAP,degraded by proteasome (PSMB) in cytoplasm,Degradation in the proteasome,The components of the proteasome include MECL-1, PSMB8, PSMB9. Structure: 20S 26S Function: Degradation of protein,Cytoplasmic cellular proteins, including non-self protein

32、s are degraded continuously by a multicatalytic protease of 28 subunits,Proteasome, the Cytosolic Meat Grinder That Chops Up Proteins,ENDOPLASMIC RETICULUM,CYTOSOL,Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I,PSMB,TAP,Transporter-associated with a

33、ntigen processing (TAP1 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,Class II-associated invariant chain peptide (CLIP),(-Ii)3 complexes directed towards endosomes by invariant chain,C

34、athepsin L degrades Invariant chain CLIP blocks groove in MHC molecule,MHC Class II containing vesicles fuse with antigen containing vesicles,HLA-DM catalyses the removal of CLIP,MIIC compartment,HLA-DM Replaces CLIP with a peptide antigen using a catalytic mechanism (i.e. efficient at sub-stoichiom

35、etric 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- peptide complexes,MHC-II Goes from Golgi (G

36、) to MHC-II Compartment (MIIC) Where Peptide Loading Occurs,Two antigen-processing pathways,3. Cross-presentation,Class MHC molecules also present exogenous antigens to CD8+T cells Class MHC molecules also present endogenous antigens to CD4+T cells,Cross-presentation: Do classical MHC class I and cl

37、ass II Presentation explain antigen presentation fully? Problem 1: Classical MHC class I presentation would require DCs to get infected and produce peptides in the DC cytoplasm. However, many viruses do NOT infect dendritic cells and still activate cytotoxic CD8+ T cells. There must be a way that de

38、ndritic cells can use intracellular peptides produced in other cells to activate cytotoxic T cells. Problem 2: Phagocytosed pathogens such as Salmonella, Brucella, and Leischmania can elicit MHC class I-dependent cytotoxic CD8+ T cell proliferation. To elicit Class I responses, pathogens in phagosomes must transfer antigens into the cytosol. Problem 3: Vaccine antigens are extracellular and yet result in cytotoxic CD8+ T cell responses. Extracellular antigens must be capable of transfer int