医学免疫学英文版教学课件：Chapter 11 APC and Antigen presentation

1、Chapter 11 Antigen Presenting Cells and Antigen presentation I. APC (antigen presenting cells)Professional APCs(DCs, macrophages, B cells)Non-professional APCsII. Ags Processing and presenting pathwayMHC class I pathwayMHC class II pathwayCross presentationNon-classical antigen presentation pathwayC

2、onceptsEndogenous antigens: antigens comes outside the cellExogenous antigens: antigens synthesized within cellsAg processing: the conversion of native proteins to MHC-associated peptide fragments by APCs.Ag presentation : formation & display of MHC-Ag peptide complex on APCs .Ag capturing -Endocyto

3、sis or Internalization : Phagocytosis: particle antigens(cell, bacteria) Pinocytosis: soluble antigens Receptor-mediated endocytosis : specific antigens (FcR, C3bR, mannose receptor, BCR)YYPinocytosisPhagocytosisMembrane Igreceptor mediateduptakeYUptake of exogenous antigensComplement receptormediat

4、ed phagocytosisYFc receptor mediated phagocytosisUptake mechanisms direct antigen into intracellular vesiclesfor exogenous antigen processing Part I. Antigen presenting cellsAntigen-presenting cells: cells that can process and present antigens (MHC-peptide) to T cells nonprofessional APCs Profession

5、al APCs : 1. constitutively expressing MHC-II and co-stimulatry molecules 2. present exogenous antigens to CD4+ T cells 3. Including macrophages, dentritic cells and B cells 1. Dendritic Cell (DC) Dendritic cells are bone marrow-derived cells specialized to present antigen to B or T cells in order t

6、o initiate a primary immune response.The most efficient APCConstitutively expressed MHCII, increased by maturation/IFNInitiate primary Immune responseCross priming(交叉递呈)(1) Identification of DC: typical morphologyspinelike projection stimulate nave T cells activation Surface markers : CD1a, CD11c, C

7、D83(human) 33D1, NLDC145 (mice) high expression of MHC co-stimulatory molecules-CD80,CD86 (2) Source of DC: Production of type I interferon in stimulation of viral infection hemopoieticstem cellplasmacytoid dendritic cells, pDC(DC2) Classical dentritic cell, or Myeloid dendritic cells，mDC (DC1) Myel

8、oid progenitorAntigen presentation(3)Classification/Distribution of DC : DC in lymphoid tissue: Interdigitating DC(IDC) , Follicular DC (FDC) DC in non lymphoid tissue: Langerhans cell(LC) DC in body fluid: veiled cell, Blood DCinterdigitating DC (IDC）Express high level of MHC-I,MHC-II molecules and

9、 B7, lack of FcR and CR, can stimulate T cells.FDCB cellfolicular DC（FDC）Lie in follicle of LN, no expression of MHCII, high level of FcR and C3bR, present antigens to B cells. Langerhans cells(LC)Birbeck particlelie in the epithelia of the skin and gastrointestinal and respiratory tracts, express F

10、cR and C3bR. After uptaking antigens, migrating to draining LN and becoming IDC.(4) Activation and Maturation of DC Antigen capture, processing and presentPre-DCbloodNon-lymphoid tissuedifferentiationImmature DCDistributeWidely distributed in the body, resident DCPossess ability of Ag capture and pr

11、ocess Cytokines and AgDC mature and move into lymphoid tissueability of Ag capture and processing decrease while its ability of Ag presenting increasemigratory DCMature DCChanges of DC during its migrationAbility of uptaking and processing antigens decrease.Ability of antigen presentation increase.E

12、xpress high level of MHC, co-stimulatory molecules(CD80,CD86), Ads(ICAM-1).Ability to stimulate nave T cell activation increase.DC:The most efficient APC initiate immune response of native T cellsCross priming: DCs can ingest infected cells and present antigens from these cells to CD8+T cells.2. Mac

13、rophages: one of the most activated and widely distributing cells in our body numerous lysosomes in their cytoplasmEnzymes and secretionsCell receptors:Markers: F4/80,CD68,CD14monocytes and macrophagesmacrophageTissuesBloodFunction : engulf and digest phathogen: Present antigen Ag capturing: recepto

14、rs mediated phagocytosis3. Secrete the cytokines:Kill the targeted cells :TNFRegulate Immune response: IL-1,6,8,12Inflammation :IL-1,8 3. B cellsFunctionsMediate humoral immune responsePresent antigens to T cellUptake of Ags: Soluble Ag-pinocytosis Specific receptor-mediated endocytosisPart II Ag Pr

15、ocessing and presentation MHC class II pathway -exogenous antigensMHC class I pathway -endogenous antigensCross presentationMHC class II pathway 1. Capture of exogenous Ag 2. Processing of Ag3. Synthesis and transportation of MHC II molecules4. Peptide loading of MHC II molecules5.Presenting to CD4+

16、 T cells 1. Capture of exogenous Ag endocytosis: phagocytosis: particles or granules pinocytosis: liquids receptor-mediated endocytosis: efficient Form endosome 2. Processing of Ag endosome + lysosome Ag antigen peptides(10-30aa) CathepsinProteases produce 24 amino acid long peptides from antigensDr

17、ugs that raise the pH of endosomes inhibit antigen processingEndosomesExogenous pathwayIncreasein acidityCell surfaceTo lysosomesUptakeProtein antigensIn endosomeCathepsin B, D and L proteases are activated by the decrease in pH3. Synthesis and transportation of MHC II molecules Synthesis of MHC II

18、molecules in ER Ii chain (Ia assciated invariant chain) -a trimer bind with 3 molecules of MHC II promote formation of MHC Preventing other peptide from combining with MHC II molecules within ER Leading MHC II molecules into endosome from ER Endosome (MIIC： MHC class II comparment) Ii: invariant cha

19、in CLIP : class II associated invariant chain peptideEREndosome4. Peptide loading of MHC II molecules Ii-MHC II molecules protease Ii chain cleaving CLIP-MHC II molecules HLA-DM CLIP releasingAntigen peptide-MHC II complexesCLIP : class II associated invariant chain peptideEndosomesCell surfaceUptak

20、eClass II associated invariant chain peptide (CLIP)(inv)3 complexesdirected towardsendosomes byinvariant chainCathepsin L degrades Invariant chainCLIP blocks groove in MHC moleculeMHC Class IIcontaining vesiclesfuse with antigencontaining vesiclesRemoval of CLIP?How can the peptide stably bind to a

21、floppy binding site?Competition between large number of peptidesHLA-DM catalyses the removal of CLIPMIIC compartmentHLA-DMReplaces CLIP with a peptide antigen using a catalytic mechanism (i.e. efficient at substoichiometric levels)editing：HLA-DO may also play a role in peptide exchangeSequence in cy

22、toplasmic tail retains HLA-DM in endosomesHLA-DMHLA-DR5.Presenting to CD4+T cellsantigen peptide-MHC II molecuels presented on cell membrane by exocytosisMHC I pathway1. Processing of endogenous Ag2.transporting of antigen peptide into ER3.peptide loading of MHC I molecules4. Presenting to CD8+ T ce

23、llsProcessing of endogenous Ag proteosome : 26S ( 20S, 19S) Proteosome subuni, beta type, PMSB: PSMB Ag antigen peptides(8-13aa)2.transporting of antigen peptide into ERTAP(transporter associated with antigen processing): Consisting of TAP1 and TAP2 ATP dependent transporter Selective transporting E

24、R membraneLumen of ERCytosol TAP(transporter associated with antigen processing)TAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideER membraneLumen of ERCytosolTAP-1TAP-2PeptideATP-

25、binding cassette(ABC) domainHydrophobictransmembranedomainPeptide antigensfrom proteasome transporting of antigen peptide into ERERCalnexin bindsto nascentclass I chainuntil 2-M bindsTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2Pepti

26、deTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideTAP-1TAP-2PeptideB2-M binds and stabilises floppy MHCTapasin, calreticulin, TAP 1 & 2 form a complex with the floppy MHCCytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compact3. peptide loading of MHC I molecules ER

27、: antigen peptideMHC I complexes4. Presenting to CD8+T cells antigen peptide-MHC I molecuels presented on cell membrane by exocytosis Ag(cytosolic protein) Proteasome proteolytic degradation Ag peptide TAP complex transporting into ER antigen peptide-MHC I molecule Golgi complex exocyotsis Present t

28、o CD8+ T cellsFeatureClass II MHC pathwayClass I MHC pathwayComposition of stable peptide-MHC complexPolymorphic and chains, peptidesPolymorphic and 2- microglobulin, peptidesTypes of APCsDCs, mononuclear phgocytes, B cells, epithelial cells and thymic epitheliumAll nucleated cellsResponsive T cells

29、CD4+T cells CD8+T cellsSource of protein antigensEndosomal/ lysosomal proteins (mostly internalized form extracellular environmentCytosolic proteins (mostly synthesized in the cells, may enter cytosol from phagosomes)Enzymes responsible for peptide generationEndosomal and lysosomal proteasesCytosolic proteasomeSite of peptide loading of MHCSpecialized vesicular compartmentEndoplasmic reticulumMolecules involved in transport of pe