醫(yī)學(xué)免疫學(xué)課件：8.APC and Ag presentation

1、IMMUNOLOGY Antigen-Presenting Cells and Antigen Presentation chapter Introduction Antigen-presenting cells Antigen processing and presentation Contents Introduction A variety of cell types which carry antigen in a form (antigenic peptide-MHC molecule complex) that can stimulate lymphocytes. It is al

2、so known as accessory cell (A cell). Dendritic cells, monocytes/macrophages and B cells are professional APCs. I. Antigen-presenting cell, APC APC染色彩圖 Antigen-presenting cells Dendritic cellsMacrophagesB cells Non-professional APC Endothelial cell (EC) Fibroblastic cell Activated T cell Target cells

3、 (such as tumor cell, virus infected cells) express MHC I and present endogenous Ag to CD8+ T cells Under some circumstances, they can express MHC II and present Ags Activation of CD8+ T cells: a. Th-dependent b. Th-independent: virus infected DC that highly express co- stimulatory molecules can dir

4、ectly stimulate CD8+ T cells. 細(xì)胞名稱(chēng) 體內(nèi)分布 MHC-II FcR C3R Birbeck 顆粒 DC 細(xì)胞 濾泡 DC 淋巴濾泡 +/- + + - 并指狀細(xì)胞 同上,淋巴組織 + - - - 胸腺依賴(lài)區(qū) 胸腺 DC 胸腺 + + ? + 朗罕細(xì)胞 表皮粒層及基層 + + + + 胃腸上皮層 間質(zhì)性 DC 實(shí)質(zhì)性器官間質(zhì) + ? ? + 的毛細(xì)血管附近 隱蔽細(xì)胞 淋巴結(jié)輸入管 + ? ? - 單核/巨噬細(xì)胞 全身組織,器官 +/- + + - B 細(xì)胞 外周血,淋巴結(jié) + + + - CTL 的靶細(xì)胞 全身有核細(xì)胞 MHC-I 分子 幾類(lèi)主要幾類(lèi)主要APC的

5、分布及其主要特性的分布及其主要特性 II. Antigen presentation The process by which certain cells in the body (APC) express antigen peptide-MHC molecule complex on their cell surface in a form recognizable by T lymphocytes. Antigen-presenting cells I.Dendritic cells (D cells) 1. Surface markers MHC class I/II molecules

6、 CD1a, CD11c, CD83 (human) 33D1, NLDC145 (mouse) Co-stimulatory molecules: B7.1(CD80)/B7.2(CD86), CD40, CD44, CD54 L 單 核 細(xì) 胞 巨 噬 細(xì) 胞 中 性 粒 細(xì) 胞 B 細(xì) 胞T細(xì) 胞 N K 細(xì) 胞 髓 系 D C BT N K 髓 系 D C 淋 巴 系 D C 淋 巴 系 前 體 細(xì) 胞 髓 系 前 體 細(xì) 胞 多 能 造 血 干 細(xì) 胞 GM-CSF TNF-a IL-4 2. Sources of DC HSC Myeloid progenitor Lymphoid

7、 progenitor Myeloid DC Mo macrophage Myeloi d DC PMN Lymphoid DC 3. Classification of DC 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) Interdigitating DC (IDC) Der

8、ived 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. Derived from interstitial DC; MHC -, highly express FcR, C3bR; Locate in lymph follicles which are rich

9、in B cells; Main APC to induce secondary immune response; involved in the generation and maintenance of memory B cells. 2) Follicular DC (FDC) 3) Langerhans cells (LC) Immature DC Found in the epidermis (skin) and mucous membranes; MHC I and IIhigh, highly express FcR and C3bR, Birbeck particle (due

10、 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 Monocytes are the common precursor of macrophage and DC Phenotype: high expression of receptors related to phagocytosis (FcR, CR, mannose

11、 receptor); low expression of CD54, CD40, CD80; CD86 and MHC II Cellular organlle: MHC calsscompartment, lysosome, Endosome Cytokine: Chemokine and proinflammatory CK such as IL- 1, IL-6, IL-15, TNF- secreted by LC Function: Powerful ability to capture and process Ags, but weak ability to stimulate

12、T cells (or weak ability to present Ags); induction of immune tolerance . (2) Immature DC (3) Mature DC Phenotype: low expression of receptors related to phagocytosis (FcR, CR, mannose receptor); high expression of MHC I/II ,CD54, CD40, CD80, CD86 ; CD1a and CD83+ . Function: weak ability to capture

13、 and process Ags, powerful ability to present Ags. Dendritic Cell Maturation 5. DC in immune activation and immune tolerance 1) DC in immune 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 cyto

14、kines IL-12 2) Induce immune tolerance n Central tolerance: induced by negative selection of T cells in the thymus. n Peripheral tolerance: immature DC capture autoantigen when they migrate from non- lymphoid tissue to T cell area of secondary lymphoid tissue, and induce peripheral tolerance. Bone m

15、arrow Blood Tissue HSC造血干細(xì)造血干細(xì) 胞胞 Myeloid progenitor起起 源源 Pre-monocyte Monocyte Monocyte Macrophage II. Monocytes and macrophages 1. Differentiation and distribution nMHC-I and II molecules; nCAM: LFA-3, ICAM-1, B7, CD40; nCKR細(xì)胞因子受體: M-CSFR; nFcR; nCR: CR1, CR3, CR4; nPattern-recognition receptor (P

16、RR): mannose甘露醇 receptor, scavenger清道夫 receptor, Toll-like receptor 2. Surface markers 3. Biological functions of M (1) Phagocytosis and cytotoxic activity : chemotaxis : blood-tissue opsonization: Ig, C3b, C4b a number of antimicrobial and cytotoxic substances produced by activated M can destroy ph

17、agocytosed microorganisms. Reactive oxygen intermediates, NO, proteinases. (2) Antigen processing and presentation: phagocytosis pinocytosis receptor-mediated endocytosis內(nèi)吞作用 (3) Secretion of soluble factors to regulate immune response enzymes: lysozyme, myeloperoxidase, etc. cytokines: IL-1, IL-6,

18、TNF, IL-12, IL-18, etc. complement: C1C9, Bf coagulation factor, PG, LTs, ACTH, etc. phagocytosis吞噬作用吞噬作用 Opsonization 調(diào)理作用調(diào)理作用 Ag presentation Macrophages Take Up Antigen Macrophages Take Up Antigen Into Vesicles and Present Peptide Into Vesicles and Present Peptide Fragments From ProteinsFragments

19、 From Proteins in MHCin MHC- -IIII III. B cells B Cells (BCR)Take Up Antigen into B Cells (BCR)Take Up Antigen into Vesicles and Present Peptide Vesicles and Present Peptide Fragments from ProteinsFragments from Proteins in MHCin MHC- -IIII Antigen processing and presentation I. Uptake of antigens E

20、xogenous外源性外源性 antigen Endogenous內(nèi)源性?xún)?nèi)源性 antigen Y The site of pathogen replication or mechanism of antigen uptake determines the antigen processing pathway used Y Cytosolic compartment Endogenous processing (Viral antigens) Vesicular Compartment Contiguous with extracellular fluid Exogenous processi

21、ng (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 Macropinocytosis巨吞飲 Receptor-mediated e

22、ndocytosis受體調(diào)節(jié) 的內(nèi)吞作用 phagocytosis吞噬 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 1. The pathway of MHC I-associated endogenous Ag presentation endogenous antige

23、n (such as virus Ag, tumor Ag) antigen peptide（8-13 aa） Peptide/MHC-I molecule complex to surface of APC submit 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.

24、 These components are induced by IFN- and replace constitutive components to confer proteolytic properties. PSMB8 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 Endosomes Cell surface Up

25、take Class II-associated invariant chain peptide (CLIP) (a-Ii)3 complexes directed towards endosomes by invariant chain Cathepsin 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

26、MIIC compartment HLA-DM Replaces CLIP with a peptide antigen using a catalytic 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 Sequence in cytoplasmic tail retains HLA-DM in end

27、osomes HLA-DM HLA-DR MIIC compartment sorts peptide-MHC complexes for surface expression or lysosomal degradation Surface expression of MHC class II- peptide complexes Exported to the cell surface (t1/2 = 50hr) Sent to lysosomes for degradation MHC-II Goes from Golgi (G) to MHC-II Compartment (MIIC)

28、 Where Peptide Loading Occurs Loading of MHC-II With Peptides From the Exterior 3. Cross-presentation Class I MHC molecules present exogenous Ags to CD8+ T cells Cross-presentation of Ags by DC plays an important role in anti-viral infection and anti-tumor immunity. Cross-presentation: Do classical

29、MHC class I and class 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 mus

30、t be a way that dendritic 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, pat

31、hogens 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 into the cytosol to elicit class I responses. Cross-presentation: Typically MHC II antigens are extracellular and MHC I antigens are cytosolic. However, this is no longer absolutely true - examples that violate both directions exist. Th