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APC & Antigen presentation

APC & Antigen presentation. antigen-presenting cell, APC. Concept A group of immune cells, whose role is to take up, process and present antigenic peptides to T cells. Professional APC Macrophages, dendritic cells, and B cells, which can express MHC class II molecules. Non-professional APC

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APC & Antigen presentation

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  1. APC & Antigen presentation

  2. antigen-presenting cell, APC Concept A group of immune cells, whose role is to take up, process and present antigenic peptides to T cells.

  3. Professional APC • Macrophages, dendritic cells, and B cells, which can express MHC class II molecules. • Non-professional APC • Other cell type capable of expressing MHC class II molecules eg. Endothelial cells, EC Fibroblasts Activated T cell

  4. 1 Dendritic cell，DC • highly branched morphology • can active naive T cells • markers

  5. 1) Markers • CD1a, CD11c, CD83 • Pathogen receptor, FcR • MHC II • co-stimulating factors (CD80,CD86) • Adhesion molecular CD40 • CD54 (ICAM-1), etc. • secreting cytokines • IL1, IL-6, IL-12, TNF-a, IFN-a, chemokines

  6. 2) Source, distribution and classification • Source DC are bone marrow-derived • Myeloid DC • Lymphoid DC

  7. Bone marrow Blood Tissue Dendritic cell Blood dendritic cell ? Pluripotent stem cell Mycloid precursor Monocyte Indeterminate cell Macrphage

  8. Distribution and classification DCs are found in many organs throughout the body • DC in lymphoid tissue • Interdigitating cell, IDC • Follicular DC, FDC • thymic dendritic cell, TDC • DC not in lymphoid tissue • Langerhans cells • Interstitial DC • DC in body fluid • Veiled cells • Peripheral blood DC

  9. interdigitating DC, IDC IDC express high levels of MHC molecules, and are more potent antigen-presenting cells than others.

  10. FDC B cells follicular DC, FDC FDC express high levels of membrane receptors for antibody and complement. By these, FDC actives the B cells in lymph nodes.

  11. Langerhan’s cells, LC Langerhans cells found in the epidermis (skin) and mucous membranes (left), expressing high levels of FcR, receptor of complement, and MHC.Birbeck granule is the characteristic organelle. After capturing antigen in the tissues by phagocytosis or by endocytosis. DC migrate into the blood or lymph and circulate to lymphoid organs, become IDC（right）。

  12. Cell MHC-II FcR C3bR Birbeck FDC ++/-- + + -- IDC ++++(I,II) -- -- -- TDC ++ + ? + LC ++++(I,II) + + + Interstitial DC ++++ ? ? + VC +++ ? ? -- M ++/-- + + -- BL ++ + + --

  13. 3) Differentiation, development, maturing and migration • Lymphoid DC • DC in lymph, negative selection of T cells • myeloid DC • Immature • mature

  14. Four phases • Pre-DC • Monocyte, Mo • Immature DC • Uptake antigen • Express MHC • Secrete chemokines • Migration • Mature DC • Express high levels of MHC I and II, CD80, CD86, CD40, CD54, HSP, etc.

  15. 4) activation and tolerance • Activation • First signal (MHC-peptide) • Second signal (co-stimulating factors) • Adhesion molecular • Cytokines (IL-12) • Tolerance • Negative selection

  16. 2 Mononuclear phagocyte system, MPS Macrophages (Mf) are phagocytic cells of monocytic lineage residing within tissues and are particularly well equipped for effective antigen presentation.

  17. Different names in different tissues • Monocyte ( blood ) • Kupffer cells ( liver ) • Mesangial cells ( kidney glomerulus ) • Microglia ( brain ) • Alveolar macrophages ( lung ) • Histiocyte ( connective tissue )

  18. 3 抑制免疫功能 suppressor M 1 2 PGE stimulatedM activated M restedM responsiveM LFA-1 过度活化 适度活化 MHC-II 细胞增生 趋化，杀菌 提呈Ag， 激活LC， 结合TC， signal 杀瘤，杀菌 second signal: LPS/IFN-, MSF,CK, 病原体 First signal: MAF/IFN-, MSF The process of M activation

  19. markers • MHC II • CR1（CD35） • CR3（CD11b/CD18） • IgG Fc受体 • Functions • Receptors • Enzymes • Cytokines

  20. 扫描电镜显示，在感染早期，M伸出长长的伪足去捕获细菌扫描电镜显示，在感染早期，M伸出长长的伪足去捕获细菌

  21. Biologic effects of M

  22. 3 B cellbone marrow-dependent lymphocyte About 5-15% of the circulating lymphoid pool are B cells difined by the presence of surface immunoglobulin.

  23. Markers of B cells

  24. Characteristics of B cells • not actively phagocytic • Class II-positive • BCR

  25. Antigen-presenting cells

  26. ANTIGEN PROCESSING AND PRESENTATION

  27. Binding and uptake of antigen • depends 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

  28. 1 Binding and uptake of antigen • exogenous antigens • Bacteria, cells and soluble proteins • processed by APC • endogenous antigens • Produced within the cells, Such as viral proteins or tumor proteins • processed by host cell

  29. Uptake antigen by immature DC • Pinocytosis • Liquid or small granule • Receptor-mediated endocytosis • effective • selective • saturated • FCR, 甘露糖R • Phagocytosis • Large molecular or microbe

  30. Uptake antigen by MPC • Phagocytosis • Large solid or molecular complex, such as bacteria, fragment of cells, etc. • Phagecyte (mf, granulocyte) • Pinocytosis • Receptor-mediated pinocytosis • Endocytosis • Low levels of particulate or soluble antigens • exocytosis

  31. Uptake antigen by B cells • nonspecifically engulfed • BCR-mediated

  32. 2 Antigen processing • Degradation of externally- or internally- derived antigen into short peptide sequences • Association of the peptide with MHC molecules

  33. Two antigen-processing pathways

  34. MHC class I processing pathway

  35. MHC class I processing pathway Antigenic protein proteosome peptide fragment released into cytosol binds to TAP protein moves to endoplasmic reticulum(ER) Newly synthesized Class I a chain and b2 microglobulin move to ER calnexin binds to a chain peptide fragment and b2m bind to a chain release of a chain from calnexin complex moves to Golgi apparatus glycosylation in Golgi apparatus secretory vesicle plasma membrane

  36. Structure of MHC class I

  37. proteasome • LMP, low molecular weight polypeptide or large multifunctional protease • Structure: • 20S 26S • Function: • Degradation of protein

  38. 26S protease cmplex 20S proteasome twin 19S cops

  39. TAP, transporter associated with antigen processing • structure: • TAP-1 and TAP-2 • function: • transports small peptides (8-13 aa) to the ER

  40. calnexin • Structure • 88kD integral ER membrane chaperone protein • Function • Binds to a nascent MHC class I a chain after release from a ribosome into the ER lumen so that the a chain will not leave the ER until it binds both a short peptide sequence and b2 microgobulin

  41. Molecular chaperones: calnexin, calreticulin,tapasin

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