抗 原 加 工 提 呈 （ A ntigen P rocessing and P resentation ）

1. 抗 原 加 工 提 呈 （AntigenProcessingandPresentation） 张 勇 上海交通大学医学院免疫学教研室

2. B B B B B B B B B Y Y Y Y Y Y Y Y Y Y Y Y Y T T Y Y Y Cross-linking of surface membrane Ig Proliferation and antibody production Y Y No proliferation T cells do not recognize native antigens 上海交通大学医学院免疫学教研室

3. T Y Cell surface peptides of Ag presented by cells that express MHC antigens native Ag Soluble peptides of Ag Cell surface peptides of Ag Cell surface native Ag Antigens must be processed in order to be recognized by T cells Ag processing and presentation T cell response No T cell response No T cell response No T cell response No T cell response 上海交通大学医学院免疫学教研室

4. 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

5. 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

6. 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

7. 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

8. 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

9. mDC iDC high levels of class II MHC and B7 Strongly present antigens but can’t uptake antigens Low levels of class II MHC and B7 Strongly internalize antigens but have no presentation ability 上海交通大学医学院免疫学教研室

10. 2.macrophage( M) monocyte：blood macrophage：tissue 上海交通大学医学院免疫学教研室

11. 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

12. The properties of various APCs 上海交通大学医学院免疫学教研室

13. Antigenprocessing 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

14. 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

15. 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

16. 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

17. Newly synthesized MHC class I molecules Peptides need access to the ER in order to be loaded onto MHC class I molecules Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I ENDOPLASMIC RETICULUM CYTOSOL 上海交通大学医学院免疫学教研室

18. Hydrophobic transmembrane domain Lumen of ER Lumen of ER Peptide Peptide Peptide Peptide Peptide Peptide Peptide Peptide Peptide Peptide Peptide ER membrane ER membrane TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 Cytosol Cytosol ATP-binding cassette (ABC) domain Peptide antigens from proteasome Transporters associated with antigen processing (TAP1 & 2) 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

19. Peptide Peptide Peptide Peptide Peptide Peptide Peptide Peptide Peptide Peptide Peptide TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-2 TAP-1 TAP-1 TAP-1 TAP-1 TAP-1 Endoplasmic reticulum Maturation and loading of MHC class I B2-m binds and stabilises floppy MHC Tapasin, calreticulin, TAP 1 & 2 form a complex with the floppy MHC Calnexin binds to nascent class I chain until 2-m binds 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

20. Exported to the cell surface Sent to lysosomes for degradation Fate of MHC class I 上海交通大学医学院免疫学教研室

21. 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

22. 上海交通大学医学院免疫学教研室

23. 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

24. Y Y Y Uptake of exogenous antigens Membrane Ig receptor mediated uptake Y Phagocytosis Complement receptor mediated phagocytosis Pinocytosis 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

25. Cell surface Uptake Endosomes Increase in acidity To lysosomes Exogenous pathway Protein antigens In endosome 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

26. MHC class II maturation and invariant chain In the endoplasmic reticulum Invariant chain stabilises MHC class II by non- covalently binding to the immature MHC class II molecule and forming a nonomeric complex Need to prevent newly synthesised, unfolded self proteins from binding to immature MHC 上海交通大学医学院免疫学教研室

27. Cell surface Endosomes Uptake Class II associated invariant chain peptide (CLIP) (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 上海交通大学医学院免疫学教研室

28. 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

29. HLA-DM Sequence in cytoplasmic tail retains HLA-DM in endosomes HLA-DM catalyses the removal of CLIP HLA-DM Replaces CLIP with a peptide antigen using a catalytic mechanism MIIC compartment 上海交通大学医学院免疫学教研室

30. Exported to the cell surface (t1/2 = 50hr) Sent to lysosomes for degradation Surface expression of MHC class II- peptide complexes 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

31. The result of Class II MHC/peptide by an APC to a CD4+ Th cellis: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

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33. 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 processingdetermine 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

34. 内源性和外源性抗原加工途径特点比较 上海交通大学医学院免疫学教研室

35. 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