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Antigen-presenting cells and antigen presentation 1.Nature of antigen-presenting cells 2. Antigen processing and presentation Antigen Presenting Cell (APC) Section 1 Nature of antigenpresenting cells Antigen-presenting cells (Antigen Presenting Cell, APC) are the immunocytes that can uptake, process and present antigens to lymphocytes. Professional APC Dendritic cells, mononuclear phagocyte system, B cells, and APC that constitutively express MHC II molecules Non-professional APC Dendritic cells DC are the most powerful APC in vivo, which can effectively stimulate naïve T cells to proliferate. Yet M and B cells can only stimulate activated or memory T cells. Multiple hematopoietic stem cell Lymphoid stem cell Myeloid stem cell Neutrophil Myeloid DC Monocyte NK cell Lymphoid DC T cell B cell Macrophage Myeloid DC Origination of dendritic cells(DC) Tissue distribution : Lymphoid DC:interdigitating DC, marginal DC Non-lymphoid DC: interstitial DC, LC, gastrointestinal epithelial DC Humoral DC: veiled cell Blood DC Differentiation and development of DC precusor immature stage (immature DC) migratory stage mature stage(mature DC) Immature DC Distribution: many solid organs and non lymphatic epithelia Major role: uptake and process antigen Normally, most DC are immature DC. Mature DC Distribution: T lymphocyte areas in lymph node, spleen, and Peyer’s node, blood Characteristics: abundantly express MHC II、 MHC I、CD80、CD86、CD40、ICAM-1、HSP、 CD1a、CD11c、CD83 Major role: antigen presentation, present peptide:MHC complex to T cells Antigen uptaking pathways by DC macropinocytosis receptor-mediated endocytosis phagocytosis 2. Mononuclear macrophages M : Origination and distribution Bone marrow pluripotent stem mononuclear cells-macrophages cells- Antigen processing and presentation of M endocytosis or internalization: phagocytosis Pinocytosis receptor-mediated endocytosis Only those M in vigorous metabolism have the capacity of antigen presentation. Macrophagocytosis mIg mediated endocytosis Complement receptor mediated endocytosis Pinocytosis Fc receptor mediated endocytosis Uptake of exogenous antigens 3 B lymphocytes Receptor-mediated endocytosis Non-specific pinocytosis Dendritic cell macrophage Staining of APC B cell Section 2 Antigen processing and presentation 1 Antigen uptaking DC capture antigens : Macropinocytosis Receptor-mediated endocytosis Phagocytosis Mononuclear macrophage capture antigens: Phagocytosis Pinocytosis Receptor-mediated endocytosis B cells captureantigens: Non-specific pinocytosis Antigen-specific mediated receptor 2. Antigen processing 1、Endogenous pathway Antigens: intracellular synthesized antigens Presenting molecules:MHC-I Processing region: Proteosome (polyubiquitination) Binding region: ER Cell surface cytoplasm Golgi complex Endoplasmic reticulum calnexin MHC Ia chain Degraded antigens proteasome Endogenous antigens Processing and presentation of endogenous antigens (1) Production of endogenous antigenic peptide Ubiquitination of endogenous antigens Degradation of endogenous antigens in proteosome Peptides containing 8-12 amino acid residues (2) Transportation of endogenous antigenic peptide Endogenous antigenic peptide enter endoplasmic reticulum: Transporter associated with antigen processing(TAP) Schematic diagram of TAP structure (3) MHC class I molecules peptide loading Class I molecules associate with chaperon: Bind to endogenous antigenic peptides Enter Golgi complex to undergo glycosylation modification Traffick to cell surface in exocytic vesicles and recognized by CD8+ T cells Membrane Antigen-MHC class 1 molecule compl β2 microglobulin Heavy chain of antigen-MHC class 1 molecule Golgi complex β2 microglobulin Calnexin Endogenous antigen Proteasome Antigenic peptide Presentation of endogenous antigens 2. Presenting pathway of antigens(Exogenous pathway) Antigen: extracellular antigens Presenting molecules: MHC-II Processing region: endosome Binding region: MIIC、CIIV exogenous Cell surface Exogenous antigens Fusion Late endosome Early endosome Antigen degradation Golgi complex MHC class 2 molecule Endoplasmic reticulum Ii chain Processing and presentation of exogenous antigens Antigen processing compartment Endosome MHC class II、HLA-DM, and exogenous antigenic peptide are found in abundance. (2)Degradation of protein antigen Peptides containing 12-20 amino acid residues Endopeptidase Exopeptidase MHC class II molecules are transported from ER to endosome. Calnexin Ia associated invariant chain(Ii chain): Class II associated invariant chain peptide (CLIP) Form nonamer with , chain Enter endosome through transGolgi network Function of Ii To prevent degradation of MHC class II molecule during its transportation CLIP binds to the grooves in MHC class II molecule (4)Ii degradation in endosome (5)Class II molecules peptide loading Class II molecules peptide loading (6)Presentation of exogenous antigens Exocytic vesicles Expressed on APC Recognized by CD4+ T cells Antigen Phagocytosis Antigen Antigenic peptide-MHC class 2 molecule complex internalization B cell Macrophage Endosome/lysosome Golgi complex ER αβIi complex Ii chain Antigenic peptide-MHC class 2 molecule complex Presentation of exogenous antigens Comparison of endogenous and exogenous antigen-presenting pathway Characteristics Endogenous pathway Presenting molecule Responding T cells MHC-I CD8+ T cells Antigen resources endogenously synthesized exogenous pathway MHC-II CD4+ T cells exogenous uptaken Synthesizing region of antigen peptides Chaperon Presenting cells proteosome Calnexin, TAP, tapasin all nucleated cells endosome Calnexin, Ii chain professional APC 3. Antigen presentation 1. Basic procedure of antigen presentation CD8+ T cells Tumor cells 2.Cross presentation of antigens by MHC molecules (Cross priming pathway) Master cell types, definition and characteristics of APC Master types of professional APC Master the pathway and procedure of exogenous and endogenous antigen presentation Familiarize antigen cross presentation Understand the distribution and characteristics of various kinds of professional APC Understand development, differentiation, maturation and migration of DC