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抗原加工提呈 （Antigen Processing and Presentation） 张 勇 上海交通大学医学院免疫学教研室 T cells do not recognize native antigens Y Y Y Y Y Y Y Cross-linking of surface membrane Ig YYY Y Y Y Y Y B B B B B BB B B Proliferation and antibody production T T No proliferation 上海交通大学医学院免疫学教研室 Y Y Antigens must be processed in order to be recognized by T cells T Y native Ag Cell surface native Ag Soluble peptides of Ag Cell surface peptides of Ag presented by cells that express MHC antigens Cell surface peptides of Ag Ag processing and presentation No T cell response No T cell response No T cell response No T cell response T cell response 上海交通大学医学院免疫学教研室 Since all cells expressing either class I or class II MHC molecules can present peptides to T cells, strictly speaking they all could be designated as Antigen Presenting Cells (APC). However,……………….. 上海交通大学医学院免疫学教研室 Target cells: Cells that display peptides associated with class I MHC molecules to CD8+ Tc cells are referred to as target cells. Professional antigen presenting cells (APC): Cells that display peptides associated with class II MHC molecules to CD4+ Th cells are called APC. 上海交通大学医学院免疫学教研室 APCs: highly specialized cells Uptake and process antigens Express co-stimulatory molecules ( B7 ) Express class II MHC molecules Present antigenic peptide to CD4+ T-cell the main APCs are: dendritic cells, macrophages and B cells. 上海交通大学医学院免疫学教研室 The 3 types of APCs Constitutively express a high level of MHC II and the co-stimulatory protein,B7. the most effective APC must be activated by the process of phagocytosis before expressing class II MHC and B7. Constitutively express class II MHC but must be activated to produce B7. 上海交通大学医学院免疫学教研室 1. dendritic cell (DC) discovered in 1973 Tissue –resident DC Immature DC(iDC) surface receptors recognize microbes migrate to local lymph nodes Within lymph nodes DC mature DC(mDC) present antigens to T cells in MHC molecules 上海交通大学医学院免疫学教研室 iDC mDC Low levels of class II MHC and B7 high levels of class II MHC and B7 Strongly internalize antigens but have no presentation ability Strongly present antigens but can’t uptake antigens 上海交通大学医学院免疫学教研室 2. macrophage( M) monocyte：blood macrophage：tissue 上海交通大学医学院免疫学教研室 3. B lymphocyte • BCR (smIg): take up soluble antigens efficintly • Constitutively express class Ⅱ MHC • Inducible expression of B7 上海交通大学医学院免疫学教研室 The properties of various APCs 上海交通大学医学院免疫学教研室 Antigen processing and presentation antigen processing protein antigen is degraded into peptide antigen presentation association of peptide with MHC and transportation of MHC-peptide complex to the cell membrane 上海交通大学医学院免疫学教研室 endogenous antigens ： proteins that are synthesized within the cytoplasm of the cell. Examples: viral proteins, tumor antigens exogenous antigens：antigens originate outside the cell. Examples: bacteria proteins 上海交通大学医学院免疫学教研室 Processing and Presentation of Endogenous Antigens (MHC class I pathway) 上海交通大学医学院免疫学教研室 Degradation in the proteasome Cytoplasmic cellular proteins, including non-self proteins are degraded continuously by a multicatalytic protease of 28 subunits The components of the proteasome include MECL-1, LMP2, LMP7 LMP2 & 7 encoded in the MHC Proteasome cleaves proteins after hydrophobic and releases peptides into the cytoplasm 上海交通大学医学院免疫学教研室 Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I ENDOPLASMIC RETICULUM Newly synthesized MHC class I molecules CYTOSOL Peptides need access to the ER in order to be loaded onto MHC class I molecules 上海交通大学医学院免疫学教研室 Transporters associated with antigen processing (TAP1 & 2) Hydrophobic transmembrane domain Lumen of ER Peptide ER membrane Cytosol Peptide Peptide Peptide antigens from proteasome ATP-binding cassette (ABC) domain Transporter has preference for >8 amino acid peptides with hydrophobic C termini. 上海交通大学医学院免疫学教研室 Maturation and loading of MHC class I Peptide Peptide Peptide Endoplasmic reticulum B2-m Calnexin binds binds and to nascent stabilises class I chain floppy until 2-m binds 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 上海交通大学医学院免疫学教研室 Fate of MHC class I Exported to the cell surface Sent to lysosomes for degradation 上海交通大学医学院免疫学教研室 The presentation of Class I MHC/ peptide by a target cell to a CD8+ Tc cell results in the proliferation and subsequent differentiation of a Tc into a killer/effector cell. The Tc can then participate in TARGET CELL KILLING. Target cell “kiss of dead” 上海交通大学医学院免疫学教研室 上海交通大学医学院免疫学教研室 Processing and Presentation of Exogenous Antigens (MHC class II pathway) 上海交通大学医学院免疫学教研室 Uptake of exogenous antigens Membrane Ig receptor mediated uptake Y Phagocytosis Complement receptor mediated phagocytosis Pinocytosis Y Fc receptor mediated phagocytosis Uptake mechanisms direct antigen into intracellular vesicles for exogenous antigen processing 上海交通大学医学院免疫学教研室 Exogenous pathway Cell surface Uptake Protein antigens In endosome Endosomes Increase in acidity To lysosomes Cathepsin B, D and L proteases are activated by the decrease in pH Proteases produce 15~30 amino acids long peptides from antigens 上海交通大学医学院免疫学教研室 MHC class II maturation and invariant chain In the endoplasmic reticulum Invariant chain stabilises MHC class Need to prevent newly II by non- covalently binding to the synthesised, unfolded self proteins from binding immature MHC class II molecule and forming a nonomeric complex to immature MHC 上海交通大学医学院免疫学教研室 Class II associated invariant chain peptide (CLIP) Cell surface Uptake (Ii)3 complexes directed towards endosomes by invariant chain Endosomes Cathepsin L degrades Invariant chain CLIP blocks groove in MHC molecule MHC Class II containing vesicles fuse with antigen containing vesicles 上海交通大学医学院免疫学教研室 Removal of CLIP ? How can the peptide stably bind to a floppy binding site? Competition between large number of peptides 上海交通大学医学院免疫学教研室 HLA-DM catalyses the removal of CLIP HLA-DM Replaces CLIP with a peptide antigen using a catalytic mechanism HLA-DM MIIC compartment Sequence in cytoplasmic tail retains HLA-DM in endosomes 上海交通大学医学院免疫学教研室 Surface expression of MHC class IIpeptide complexes Exported to the cell surface (t1/2 = 50hr) Sent to lysosomes for degradation MIIC compartment sorts peptide-MHC complexes for surface expression or lysosomal degradation 上海交通大学医学院免疫学教研室 The result of Class II MHC/peptide by an APC to a CD4+ Th cell is: ACTIVATION and PROLIFERATION of the Th cell and then “help” other immuno-cells to activate. 上海交通大学医学院免疫学教研室 上海交通大学医学院免疫学教研室 Separate antigen-presenting pathways are utilized for endogenous (green) and exogenous (red) antigens. The mode of antigen entry into cells and the site of antigen processing determine whether antigenic peptides associate with class I MHC molecules in the rough endoplasmic reticulum or with class II molecules in endocytic compartments. 上海交通大学医学院免疫学教研室 内源性和外源性抗原加工途径特点比较 特点 内源性抗原加工途径 外源性抗原加工途径 提呈抗原肽的 MHC 分子 I 类分子 II 类分子 应答的 T 细胞 CD8+ T 细胞 CD4+ T 细胞 抗原来源 内源性 外源性 抗原肽产生部位 胞内蛋白酶体 内体、溶酶体 MHC 荷肽部位 内质网腔 CIIV 或 MIIC 伴随蛋白 钙联素，TAP，tapasin 钙联素，Ii 链 提呈细胞 所有有核细胞 专职 APC 上海交通大学医学院免疫学教研室 本章要求： 1.掌握APC的概念、种类及生物学功能。 2.掌握内源性和外源性抗原加工提呈的过 程。 3.掌握下列常用名词： 抗原加工提呈、APC、内源性抗原、外源性抗原 上海交通大学医学院免疫学教研室