免疫细胞和免疫应答[001]

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,免疫细胞和免疫应答001,Cells of immune system,T lymphocytes,Development of T cells,Stages of T cell maturation,Positive and negative selection,Positive selection,（阳性选择）,DP cells that bind, with moderate affinity, to MHC-Ag on thymic stroma cells survive-,MHC restriction,（,MHC,限制性）,MHC I-CD8,+,T cells,MHC II-CD4,+,T cells,Negative selection,（阴性选择）,Cells that bind to MHC-Ag on thymic stroma cells (or auto-reactive T cells, ART) will undergo apoptosis,Formation of central immune tolerance,（免疫耐受）,T cell surface markers,TCR-CD3 complex,TCR,A heterodimer comprising an, and a chain or a and a chain joined by a disulfide bond.,Function: specific recognition of,peptide-MHC complex.,TCR-CD3 complex,Consists of 5 proteins that are designated as, and,.,Three dimers:,(,),The cytoplasmic domain contains ITAM (immunoreceptor tyrosine-based activation motif) YXXL/V,Function: transduction of signals that lead to T cell activation.,CD3,Main co-stimulatory molecules mediating interactions between T cells and APCs,Receptors of mitogens,(,丝裂原受体,),PHA-R,ConA-R,PWM-R,Cytokine receptor(,细胞因子受体,),Virus receptor (,病毒受体,),Leukocyte differentiation antigen(LDA,，白细胞分化抗原,) :,The cell surface markers which express or disappear on the different leukocytes in the different stage of differentiation and activation.,T Cell Surface Molecules,CD (cluster of differentiation,，分化群,),: Cell surface molecules of leucocytes that are distinguishable with monoclonal antibodies as an immunologic marker.,CD1-350,CD4 and CD8 (coreceptor),Function: 1) Help the interaction between T cell and APC and enhance the recognition of antigen by TCR; 2) help the TCR-CD3 signals transduction,CD4: MHC II Ag binding, Receptor,of HIV gp120,CD8: MHC I Ag binding,Co-stimulatory molecules,CD28: its ligands are B7 family molecules, including B7-1/2 (CD80/CD86),Function,: costimulation, activation of,T cells,CTLA-4 (CD152): homodimer, homologous to CD28.,Function,: inhibits T cell costimulation (the cytoplasmic domain contains ITIM), 2005 Elsevier,Cell adhesion molecules(,细胞粘附分子,),CAM,: A group of proteins involved in adhesion of cell to cell or cell to extra-cellular matrix (ECM), such as ICAM-1, ICAM-2, ICAM-3, VCAM-1 and PECAM etc.,Categories of CAM,1. Integrin family,（整合素家族）,2. Selectin family,（选择素家族）,3.,Cadherin,（钙粘素家族）,4. IGSF (Ig superfamily),（免疫球蛋白超家族）,5. Mucin-like family,（黏蛋白样家族）,6. Others:PNAd, CD44, CD36,III. T cell subsets,1,TCR,T cells and TCR,T cells,2,CD4,+,T and CD8,+,T cells,3,Th, Tc and Treg,4. Naive T cells,（初始型）, effector T cells,（效应性）,and memory T cells,（记忆性）,IV. Functions of T cells,1.,CD4,+,helper T cells (Th),Th0:Th cells that secrete broad spectrum of,cytokines at low level.,Th1: produce IL-2 and IFN-, but not IL-4. They are chiefly responsible for cell-mediated immune responses, but can also help B cells to produce IgG2a, but not much IgG1 or IgE;,Th2: secrete IL-4, 5, 10, 13, but not IL-2 and IFN-, are very efficient helper cells for production of antibody, especially of IgG1 and IgE ;,IV. Functions of T cells,1.,CD4,+,helper T cells (Th),Th3: produce TGF-,.,inhibit Th1 mediated immunity and inflamation,inhibit function of B,Tc,NK,Th17: secrete IL-17.,innate immunity and inflammation,2.,CD8,+,cytotoxic T cells (CTL, Tc),Function: directly kill target cells (cytotoxicity),Mechanisms:,3.,CD4,+,CD25,+,regulatory T cells (Tr),Foxp3 positive,Function:,Down-regulation of immune response by inhibiting the activation and proliferation of CD4,+,or CD8,+,T cells.,Mechanisms:,Direct inhibition by contacting target cells.,Inhibitory cytokines:IL-10,TGF-,et al., 2005 Elsevier,B cell,I. Development of B cell,B,lymphocytes refer to,B,one marrow-derived lymphocytes or,B,ursa-derived lymphocytes,About 20,of the circulating lymphoid pool are B cells.,Development of B cell in BM,. B-cell surface markers,1. BCR complex,BCR (mIg),：,V,H,V,L,-Ag,mature B cells: mIgM and mIgD.,Function,: specifically recognizes antigen.,Ig,/Ig (,CD79a/CD79b):,heterodimer cytoplasmic domains contain ITAM.,Function,: 1. transfers the signals that,lead to B cell activation,.,2.,transports the Ig,2. Co-receptors:,CD19/CD21/CD81complex,3. Co-stimulatory molecules,(1)CD40,(2)CD80/CD86,(3)ICAM-1, LFA-1,4. Other receptors,CD20:B cell marker,CD22:inhibitory receptor,CD32:Fc,R,B-cell subsets,B1 cells (,CD5,+,):,Many of the first B cells that appear during ontogeny express CD5, a marker originally found on T cells. (,express mIgM,no mIgD). They respond well to TI-Ag and may also be involved in the Ag processing and presentation to T cells.,Functions,1. produce anti-bacterial,IgM,the first line of defence against microorganisms;,2. produce polyreactive Ab clearance of denatured self components;,3. produce auto-Ab, thereby participating in the pathogenesis of some autoimmune diseases.,B2 cell,: CD5,-,B cells.,mIg: IgM, IgD,after antigenic stimulation, in,the presence of Th, they,produce more IgG,than,IgM,B1 and B2 cell,B1,B2,CD5,+,-,renewing,Self renewing,Derived from BM,Spontaneously Ig production,High,Low,Antigen,Carbohydrate,Protein,Class of Ig,IgMIgG,IgGIgM,Specificity,Multi-specificity,Mono-specificity,Somatic Hypermutation,Low/no,High,memory,-,+,NK Cells,NK cells were defined initially by their ability to lyse certain tumor cell lines and virally infected cells without prior immunization, and so mediate a form of innate (or natural) immunity that is termed,“,natural killing,”,.,I. Ontogeny and distribution of NK cell,Derive from a bone marrow precursor,large granular lymphocytes,distribution: peripheral blood, spleen,NK cells are,rare in lymph node and do not circulate through the lymph,.,II. Surface markers,1.,CD56,2. CD16 (Fc,RIII) : ADCC,3. CD2,4. CD11a/CD18 (LFA-1),They nevertheless serve to identify NK cells, which are generally CD16,+, CD56,+, CD3,-, whereas T cells are CD16,-, CD56,-, CD3,+,.,5. NK cells receptors,KAR (killer cell activation receptor,，杀伤细胞活化受体,): CD94/NKG2C,ITAM (immnoreceptor tyrosine-based activation motif,-YxxL/Vx(7-11) YxxL/V-,),ligand: saccharide,KIR (killer cell inhibitory receptor,，杀伤细胞抑制受体,): CD94/NKG2A,ITIM (immnoreceptor tyrosine-based inhibitory motif,I/VxYxxL,),ligand: class I MHC molecules,Intracellular signaling pathways coordinate inhibitory and activating signals,Downloaded from: StudentConsult (on 1 June 2006 01:58 PM), 2005 Elsevier,III. Functions of NK cells,1. Anti-infection,provide an early innate barrier to infection by eliminating infected host cell,2. Anti-tumor,kill tumor cells directly,: perforin, granular enzyme,ADCC,3. Immunoregulation,produce cytokines such as IFN-, TNF-, G-CSF,Antigen-presenting cells,抗原提呈细胞,Professional APCs :Dendritic cells; Monocytes/macrophages and B cells,Classification of APCs,Classification of APCs,Non-professional APC,Endothelial cell (EC),Fibroblastic cell,Activated T cell,Inducible expression of MHC class II molecules,Target cells,Expression of MHC,class I molecules,Bone marrow,Blood,Tissue,HSC,Myeloid progenitor,Pre-monocyte,Monocyte,Monocyte,Macrophage,IIMonocytes and macrophages,1. Differentiation and distribution,MHC-I and,II molecules;,CAM: LFA-1, ICAM-1, B7, CD40;,CKR: M-CSFR;,FcR;,CR: CR1, CR3, CR4;,Pattern-recognition receptor (PRR): mannose receptor, scavenger receptor, Toll-like receptor,2.,Surface markers,3.,Biological functions of M,(1),Phagocytosis and cytotoxic activity :,chemotaxis : blood-tissue,opsonization: Ig, C3b, C4b,a number of antimicrobial and cytotoxic substances produced by activated M, can destroy phagocytosed microorganisms.,Reactive oxygen intermediates, NO,proteinases,.,phagocytosis,(2)Antigen processing and presentation:,phagocytosis,pinocytosis,receptor-mediated endocytosis,(3) Secretion of soluble factors to regulate immune response,enzymes: lysozyme, myeloperoxidase, etc.,cytokines: IL-1, IL-6, TNF, IL-12, IL-18, etc.,complement: C1,C9, Bf,coagulation factor, PG, LTs, ACTH, etc.,Dendritic cells,(DCs,，树突状细胞,),1. Surface markers,(1) MHC class II molecule,(2) Specific marks:CD1a, CD11c, CD83 (human); 33D1, NLDC145 (mouse),(3) Co-stimulatory molecules:CD80,CD86,CD40, CD44, CD54,integrin,1,2,(4)Receptor:FcR,TLR,GM-CSF,TNF-,a,IL-4,2.,Classification of DC: origin of DC,HSC,Myeloid progenitor,Lymphoid progenitor,Myeloid DC,Mo,macrophage,Myeloid,DC,PMN,Lymphoid,DC,2.,Classification of DC:,Dendritic Cell Maturation,Migrating DC,2. Classification of DC:distribution,Lymphoid tissue DC,follicular DC (FDC), interdigitating DC (IDC), thymic DC,Non-lymphoid tissue DC,Langerhans cell, interstitial DC,Circulating DC,peripheral blood DC, veiled cell,4. Function of DC,Antigen presenting and activation of adaptive T cells,Immunoregulation,Maintainance and induction of immune tolerance,B cells,Immune Response,免疫应答,Immune Response,（免疫应答）,innate immune response(,固有免疫应答,),natural immune response,non-specific immune response,adaptive immune,response,（适应性免疫应答）,acquired immune response,specific immune response,Innate and adaptive immunity,innate immune response,Physiological barriers,skin,mucous membranes,Phagocytosis,polymorphonuclear leukocytes(PMN),macrophages Toll-like receptor 4/LPS,Natural killer(NK) cell,Complement , Acute phase proteins,innate immune response,innate immune response,(,Lung) Macrophage Attacking E. coli,Adaptive immune response,Immune Response,Features of Innate and Adaptive Immunity,T cell-mediated immune response,Types of intracellular microbes combated by T cell-mediated immunity,Phases of T cell responses,Three phases,Antigen recognition phase,Activation ,proliferation and differentiation phase,Effector phase,. Antigen recognition,1 Ag presentation by APC,Antigen processing and presentation,I. Uptake of antigens,Y,The site of pathogen replication or mechanism of antigen uptake determines the antigen processing pathway used,Y,Cytosolic compartment,Endogenous processing,(Viral antigens),Vesicular Compartment,Contiguous with extracellular fluid,Exogenous processing,(Streptococcal, Mycobacterial antigens),Distinct mechanisms of antigen generation are used to raise,T cells suited to the elimination of endogenous or exogenous pathogens,INTRACELLULAR REPLICATION,EXTRACELLULAR OR,ENDOSOMAL REPLICATION,1. The pathway of MHC I-associated endogenous Ag presentation,endogenous antigen (such as virus Ag, tumor Ag),antigen peptide,（,8-13 aa,）,Peptide/MHC-I molecule complex,to surface of APC,submit to CD8,+,T,transported to,endoplasmic reticulum,by TAP,degraded by proteasome (LMP) in cytoplasm,Degradation in the proteasome,The components of the proteasome include MECL-1, LMP2, LMP7.,These components are induced by IFN-,and replace constitutive components to confer proteolytic properties.,LMP2 & 7 encoded in the MHC,Proteasome cleaves proteins after hydrophobic and basic amino acids and releases peptides into the cytoplasm,Cytoplasmic cellular proteins, including non-self proteins,are degraded continuously by a multicatalytic protease of 28 subunits,Proteasome, the Cytosolic Meat Grinder That Chops Up Proteins,ENDOPLASMIC RETICULUM,CYTOSOL,Peptide antigens produced in the cytoplasm are physically separated from newly formed MHC class I,Newly synthesised,MHC class I molecules,Peptides need,access to the ER in,order to be loaded onto MHC class I molecules,LMP,TAP,ER membrane,Lumen of ER,Cytosol,Transporter-associated with,antigen processing (TAP1 & 2),Transporter has preference for 8 amino acid peptides,with hydrophobic C termini.,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,ER membrane,Lumen of ER,Cytosol,TAP-1,TAP-2,Peptide,ATP-binding cassette,(ABC) domain,Hydrophobic,transmembrane,domain,Peptide antigens,from proteasome,Endoplasmic reticulum,Calnexin binds,to nascent,class I,chain,until,2-M binds,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,TAP-1,TAP-2,Peptide,2-M binds and stabilises floppy MHC,Tapasin, calreticulin, TAP 1 & 2 form a complex with the floppy MHC,Cytoplasmic peptides are loaded onto the MHC molecule and the structure becomes compact,Maturation and loading of MHC class I,2. The pathway of MHC II-associated exogenous Ag presentation,Exogenous 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 DM,Degrade into 13,18aa peptide + releasing the CLIP and allowing other,peptide to bind,Ag peptide/MHC class II molecule complex,transport to the surface of APC, recognized by CD4,+,T,Phagocytosis, pinocytosis,FcR-phagocytosis,Y,Y,Pinocytosis,Phagocytosis,Membrane Ig,receptor mediated,uptake,Y,Uptake of exogenous antigens,Complement receptor,mediated phagocytosis,Y,Fc receptor mediated phagocytosis,opsonization,Proteases produce 24 amino acid long peptides from antigens,Endosomes,Exogenous pathway,Increase,in acidity,Cell surface,To lysosomes,Uptake,Protein antigens,In endosome,Cathepsin B, D and L proteases are activated by the decrease in pH,Pathway for Peptide+MHC-II Formation, from Endocytosis Proteins into Vesicles to Formation of Peptides on MHC-II,Need 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 complex,In the endoplasmic reticulum,MHC class II maturation and invariant chain,involve 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 peptide,Endosomes,Cell surface,Uptake,Class II-associated invariant chain peptide (CLIP),(,-,I,i),3,complexes,directed towards,endosomes by,invariant chain,protease degrades Invariant chain,CLIP blocks groove in MHC molecule,MHC Class II,containing vesicles,fuse with antigen,containing vesicles,HLA-DM catalyses the removal of CLIP,MIIC compartment,HLA-DM,Replaces CLIP with a peptide antigen using a catalytic mechanism (i.e. efficient at sub-stoichiometric levels),Discovered using mutant cell lines that failed to present antigen,HLA-DO may also play a role in peptide exchange,Sequence in cytoplasmic tail retains HLA-DM in endosomes,HLA-DM,HLA-DR,MIIC compartment sorts peptide-MHC complexes for surface expression or,lysosomal degradation,Surface expression of MHC class II-,peptide complexes,Exported to the cell surface (t1/2 = 50hr),Sent to lysosomes for degradation,MHC-II Goes from Golgi (G) to MHC-II Compartment (MIIC) Where Peptide Loading Occurs,3. Cross-presentation,Class I MHC molecules present exogenous Ags to CD8,+,T cells,Cross-presentation of Ags by DC plays an important role in anti-viral infection and anti-tumor immunity.,3. Cross-presentation,4,CD1-mediated antigen presenting pathway,2, Interaction between APC and T cell,Non specific binding of APC and Tcell,Specific binding of APC and T cell,TCR-peptide-MHC,co-receptor-MHC,co-stimulatory molecules,T cell synapse or immunological synapse,Ligand-receptor pairs involved in T cell activation,Main costimulatory molecules mediating interactions between T cells and APCs,3 activation, proliferation and differentiation,The first signal,TCR-antigen peptide-MHC (double recognition),CD4-MHC II or CD8-MHC I,The second signal (co-stimulatory signal),Interactions between co-stimulatory molecules on APC and corresponding receptors on T cells,CD28/CTLA-4 B7, LFA-1ICAM-1,LFA-2LFA-3,Cytokines in T cell activation,IL-1,2,6,12,Proliferation and differentiation of T cells,1) CD4,+,T cells: Th, Tr, Treg,Th17,Tm,regulated by cytokines,2),CD8,+,T cells: Tc,Th-dependent,Th-independent,: virus infected DC that highly express co-stimulatory molecules can directly stimulate CD8,+,T cells.,Activation of CD8,+,T cells,Cytokines are required in T cell proliferation and differentiation,Activ,a,ted T cells can produce cytokines,(IL-2,4,7,10,etc.) and express cytokine receptors,that,promote T cell,s,to proliferate,and,differentiate.,4.,Effector functions of activated T cells,1,),CD4,+,T cells,Th1:,secrete IFN-, etc.,express CD40L,express FasL, kill Fas,+,target cells,effect on lymphocytes: IL-2,effect on neutrophil: TNF-,Th2:,promote B cell growth and Ig production,mediate hypersensitivity,Th17:,IL-17,Il-8,TNF-:,enhance leukocyte recruitment and inflammation,Activate macrophages,Two types of cell-mediated immunity,Cell-mediated immunity against intracellular microbes,Activation of macrophages by T lymphocytes,Cytotoxicity,: kill target cells,a. necrosis: perforin and granzyme,b. apoptosis: granzyme, FasL,Characteristics of CD8,+,T cell cytotoxicity,a.,Specificity,b. MHC I restriction,c. High efficiency,2),CD8,+,T cells,Downloaded from: StudentConsult (on 1 June 2006 03:50 PM), 2005 Elsevier,Mechanisms of killing of infected cells by CD8,+,CTLs,3) memory T cells,1) CD45RA,-,CD45RO,+,2) Long-lived memory to specific antigen,3) Mediate faster, stronger and more,effective immune response,4) Mechanism: low dependent on costimulatory molecules or more sensitivity to cytokines,Activation induced cell death, AICD,1) Activation induced cell death,Activated T cells express FasL that induce apoptosis of Fas positive T cells.,2) Passive cell apoptosis,Ag, survival signals and growth factors ,Activation-induced death of T cells,B cell-mediated humoral immune response,Humoral immunity is mediated by antibodies and is the arm of the adaptive immune response that functions to neutralize and eliminate,extracellular microbes,and,microbial toxins,.,Phases and types of humoral immune responses,1) Phases,Antigen recognition phase,Activation, proliferation and differentiation phase,Effector phase,2) Types,Response to TD-Ag,Response to TI-Ag,Phases of humoral immune responses,Effector phase,1) B cells recognize TD-Ag,a. BCR directly recognizes B cell epitopes,b. Ig,/Ig,transfer the first signal,c.,Effect of,coreceptors (CD21/CD19/CD81),d. Signalling pathways,The role of coreceptor (CD19/CD21/CD81) in B cell activation,2) Role of Th cells in humoral immune response to TD-Ag,For a protein Ag to stimulate Ab response, B cells and Th cells specific for that Ag must come together in lymphoid organs and interact in a way that stimulates B cell proliferation and differentiation.,a.