浙江大学医学免疫学经典课件免疫11apc

1、antigen-presenting cells and antigen presentationxiaojian wanginstitute of immunology zhejiang u nintroduction nantigen-presenting cellsnantigen processing and presentationcontentsi. antigen-presenting cell, apcantigen-presenting cells are required for t cell activationna variety of cells specialize

2、d in capturing 、processing and present the antigen to the t lymphocytes, causing either tolerance or immunity. nthese cells are name as anitgen presenting cell, apcn dendritic cells, monocytes/macrophages and b cells are professional apcs.i. antigen-presenting cell, apcapc染色彩图antigen-presenting cell

3、sdendritic cellsmacrophagesb cells non-professional apcnendothelial cell (ec)nfibroblastic cellnactivated t cellunder some circumstances, they can express mhc ii and present agsii. antigen presentation the process by which apc express peptide-mhc on their cell surface in a form recognizable by lymph

4、ocytes.antigen-presenting cellsi. dendritic cellsnhighly branched morphologyncan active naive t cellsnmarkersthe nobel prize in physiology or medicine 2011拉尔夫拉尔夫斯坦曼（斯坦曼（ralph m. steinman）【已故已故】1943年出生于加拿大蒙特利尔，在麦吉年出生于加拿大蒙特利尔，在麦吉尔大学学习生物学和化学。之后在美国哈佛医学院学习医学，尔大学学习生物学和化学。之后在美国哈佛医学院学习医学，1968年获得医学博士学位（年获得医学

5、博士学位（md）。于）。于1970年被纽约洛克菲勒大学接纳，从年被纽约洛克菲勒大学接纳，从1988年起成为免疫学教授。担任该校免疫年起成为免疫学教授。担任该校免疫学与免疫性疾病中心主任。学与免疫性疾病中心主任。发现树突状细胞发现树突状细胞dendritic cells, dc是启动适应性免疫应答是启动适应性免疫应答的关键细胞的关键细胞r. m. steinman and z. a. cohn.j. exp. med. 137, 11421162; 1973 1. surface markersnmhc class i/ii moleculesncd1a, cd11c, cd83 (human)

6、n33d1, nldc145 (mouse)nco-stimulatory molecules: b7.1(cd80)/b7.2(cd86), cd40, cd44, cd542. sources of dc单 核 细 胞巨 噬 细 胞中 性 粒 细 胞b 细 胞t 细 胞n k 细 胞髓 系 d cbtn k髓 系 d c淋 巴 系 d c淋 巴 系 前 体 细 胞髓 系 前 体 细 胞多 能 造 血 干 细 胞gm-csftnf-ail-4hscmyeloid progenitorlymphoid progenitormyeloid dc momacrophagemyeloid dcpmn

7、lymphoid dc3. distribution and classification of dcdcs are found in many organs throughout the body ndc in lymphoid tissue -lymphoid tissue dcninterdigitating cell, idcnfollicular dc, fdcnthymic dendritic cell, tdcndc not in lymphoid tissue-non-lymphoid tissue dcnlangerhans cells ninterstitial dcndc

8、 in body fluid-circulating dcnveiled cellsnperipheral blood dcnlocated in lymph follicles which are rich in b cells;nderived from interstitial dc;nhighly express fcr, cr1 and cr2;ninvolved in the generation and maintenance of memory b cells.1) follicular dc (fdc)follicular dc, fdcb cellsfdcfdc expre

9、ss high levels of membrane receptors for antibody and complement. by these, fdc actives the b cells in lymph nodes.2) interdigitating dc (idc)nmain apc to induce primary immune response;nderived from langerhans cells;nfcr- and c3br-, mhc i and iihigh;ndistributed mainly in the t cell area of seconda

10、ry lymphoid tissue, present ags to t cells.3) langerhans cells (lc)nfound in the epidermis (skin) and mucous membranes;nmhc i and iihigh, highly express fcr and c3br, birbeck particle (due to langerin expression);npowerful ability to capture and process ags and migration to lymph node after activati

11、on.langerhans idc4. development of myeloid dcnfour phasesnpre-dcnmonocyte, monimmature dc nuptake antigennmigrationnmature dcnexpress high levels of mhc i and ii, cd80, cd86, cd40, cd54, hsp, etc.nimmature dc phenotype: high expression of receptors related to phagocytosis (fcr, cr, mannose receptor,

12、 dc-sign); low expression of cd54, cd40, cd80; cd86 and mhc ii, cd14- function: 1) strong capacity to ingest and process ags, but weak ability to present ags 2) induction of immune tolerance 3) sensing of infectious agents by tlr (pattern recognition receptors) nmature dc phenotype: low expression o

13、f receptors related to phagocytosis (fcr, cr, mannose receptor); high expression of cd54, cd40, cd80, cd86 and mhc ii; cd83+ and cd25+ function: weak ability to capture and process ags, powerful ability to present ags. dendritic cell maturation mhc ii5. dc in immune activation and immune tolerance1)

14、 dc in immune activation present antigen and activate t cells the first signal mhc ii-ag: cd4+ t cells mhc i-ag: cd8+ t cells the second signal co-stimulating molecules cytokines il-12 n peripheral tolerance: immature dc capture autoantigen when they migrate from non-lymphoid tissue to t cell area o

15、f secondary lymphoid tissue, and induce peripheral tolerance. ncentral tolerance: induced in negative selection of t cells in the thymus.n 2) dc induce immune tolerance bone marrow blood tissuehscmyeloid progenitorpre-monocytemonocyte monocyte macrophage ii mononuclear phagocyte system (mps) 1. diff

16、erentiation and distributiondifferent names in different tissuesnmonocyte ( blood )nkupffer cells ( liver )nmesangial cells ( kidney glomerulus )nmicroglia ( brain )nalveolar macrophages ( lung )nhistiocyte ( connective tissue )nmhc-i and ii molecules;ncam: lfa-1, icam-1, b7, cd40;nfcr;ncr: cr1, cr3

17、, cr4;npattern-recognition receptor (prr): mannose receptor, scavenger receptor (cd91), toll-like receptors 2. surface markers3. biological functions of m antigen processing and presentation phagocytosis pinocytosis receptor-mediated endocytosis antimicrobial and cytotoxic activity: a number of anti

18、microbial and cytotoxic substances produced by activated m can destroy phagocytosed microorganisms. reactive oxygen intermediates, nitric oxide. n secretion of soluble factors: enzymes: lysozyme, myeloperoxidase, etc. cytokines: il-1, il-6, tnf, il-12, il-18, etc. complement: c1c9, bf coagulation fa

19、ctors, pg, lts, acth, etc.phagocytosismacrophageag presentationmacrophages take up antigen macrophages take up antigen into vesicles and present peptide into vesicles and present peptide fragments from proteinsfragments from proteinsin mhcin mhc- -iiiiiii. b cellsbone marrow-dependent lymphocyteabou

20、t 5-15% of the circulating lymphoid pool are b cells defined by the presence of surface immunoglobulin (ig).iii. b cellsb cells (bcr)take up antigen into b cells (bcr)take up antigen into vesicles and present peptide vesicles and present peptide fragments from proteinsfragments from proteinsin mhcin

21、 mhc- -iiiiantigen processing and presentation1.binding and uptake of antigenndepends on the physical state of the antigen and the cell type involved.2.antigen processingnmhc class i processing pathwaynmhc class ii processing pathway3.antigen presentation1 binding and uptake of antigennendogenous an

22、tigens: mhci-cd8nproduced within the cells, such as viral proteins or tumor proteinsnprocessed by host cellnexogenous antigens: mhcii-cd4nproduced out of the cells, bacteria, cells and soluble proteinsnprocessed by apcuptake antigen by immature dc and macrophagenpinocytosis nliquid or small granulen

23、phagocytosis large molecular or microbenreceptor-mediated endocytosisneffectivenselectivennonspecifically engulfednbcr-mediateduptake antigen by b cells2 antigen processingndegradation of externally- or internally- derived antigen into short peptide sequencesnassociation of the peptide with mhc mole

24、cules1. the pathway of mhc i-associated endogenous ag presentationtransported to endoplasmic reticulum by tapdegraded by proteasome (lmp2/7) in cytoplasm endogenous antigen (such as virus ag, tumor ag) antigen peptide（8-10 aa） peptide/mhc-i molecule complex to surface of apc present to cd8+t kill th

25、e infected or mutated cellsdegradation in the proteasomethe components of the proteasome include mecl-1, lmp2, lmp7.protein in cells including non-self proteinsare degraded continuously by a multicatalytic protease of 28 subunitsproteasome, the cytosolic meat grinder that chops up proteinsendoplasmi

26、c reticulumcytosolpeptide antigens produced in the cytoplasm are physically separated from newly formed mhc class inewly synthesisedmhc class i moleculespeptides needaccess to the er inorder to be loaded onto mhc class i moleculeslmptaper membranelumen of ercytosoltransporter-associated withantigen

27、processing (tap1 & 2)transporter has preference for 8 amino acid peptideswith hydrophobic c termini.tap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptideer membranelumen of ercyto

28、soltap-1tap-2peptideatp-binding cassette(abc) domainhydrophobictransmembranedomainpeptide antigensfrom proteasomeendoplasmic reticulumcalnexin bindsto nascentclass ia chainuntil 2-m bindstap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2p

29、eptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptidetap-1tap-2peptide2-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 compactmaturation and loading of mhc cla

30、ss i2. the pathway of mhc ii-associated exogenous ag presentationexogenous antigen newly synthesised mhc class ii molecule (in the endoplasmic reticulum) endosome ii binds in the groove of mhc class ii molecule lysosome protease m ii c phagolysosome li clip protease dmdegrade into 12 15aa peptide +

31、releasing the clip and allowing other peptide to bind ag peptide/mhc class ii molecule complextransport to the surface of apc, recognized by cd4+tphagocytosis, pinocytosis, fcr-phagocytosis bcr-receptoryypinocytosisphagocytosismembrane igreceptor mediateduptakeyuptake of exogenous antigenscomplement

32、 receptormediated phagocytosisyfc receptor mediated phagocytosisopsonizationproteases produce 24 amino acid long peptides from antigensendosomesexogenous pathwayincreasein aciditycell surfaceto lysosomesuptakeprotein antigensin endosomecathepsin b, d and l proteases are activated by the decrease in

33、phneed to prevent newly synthesised, unfolded self proteins from binding to immature mhc invariant chain stabilises mhc class ii by non-covalently binding to the immature mhc class ii molecule and forming a nonomeric complexin the endoplasmic reticulummhc class ii maturation and invariant chain invo

34、lve in the assembling and folding of mhc class ii molecule; block the groove of mhc class ii molecule; lead the assembled class ii molecule to m ii c.the functions of ii:clip：class ii-associated invariant chain peptidehla-dm catalyses the removal of clipmiic compartmenthla-dmreplaces clip with a pep

35、tide antigen using a catalytic mechanism (i.e. efficient at sub-stoichiometric levels)discovered using mutant cell lines that failed to present antigenhla-do may also play a role in peptide exchangesequence in cytoplasmic tail retains hla-dm in endosomeshla-dmhla-drmiic compartment sorts peptide-mhc complexes for surface expression orlysosomal degradationsurface