中科院细胞与分子免疫学课程chapter11ppt课件

Section IV Effector Mechanisms of Immune Responses Chapter 11 Cytokines qNomenclature : 1. Based on their cellular sources: Monocyte -Monokine; Lymphocyte-Lymphokine; 2. Because many cytokines are made by leukocytes and act on other leukocytes, they are also called interleukines. 3. In this book, we use term cytokine, which does not imply restricted cellular sources or biologic activities. Nomenclature: General Properties of Cytokines: 1. Cytokine secretion is a brief, self-limited event. 1) Cytokines are not usually stored as performed molecules. 2) When cell was activated, the synthesis of cytokines is initiated. 2 Cytokines can act in three different manners Autocrine Cytokine binds to receptor on cell that secreted it. 2. Paracrine Cytokine binds to receptors on near by cells 3. Endocrine Cytokine binds cells in distant parts of the body 3 Cytokine Actions Pleiotropy Act on more than one cell type Redundancy More than one cytokine can do the same thing (IL-2, IL-4,IL-5) Synergy Two or more cytokines cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately (IFN- and TNF) Antagonism Two or more cytokines work against each other (IL- 10 and IFN-) 4. Cytokines make functions in binding to receptor Kd: 10-10-10-12 5.External signals regulate the expression of cytokine receptor. 6. Cytokines can change the gene expression in target cells. qqFunctional Classification of CytokineFunctional Classification of Cytokine 1. Mediators and regulators of innate immunity: Secreted by mononuclear phagocytes,these members of cytokines can stimulate the early inflammations. 2. Mediators and regulators of adaptive immunity. Secreted by T lymphocytes, some of them regulate the proliferation and differentiation of lymphocytes. Recruit, activate, regulate specialized effector cells. 3. Stimulators of hematopoiesis. Are produced by bone borrow stromal cells, stimulate the growth and differentiation of immature leukocytes. Table 11-1. Comparative Features of the Cytokines of Innate and Adaptive Immunity FeaturesInnate immunityAdaptive immunity ExamplesTNF-, IL-1, IL-12, IFN- *IL-2, IL-4, IL-5, IFN- * Major cell sourceMacrophages, NK cellsT lymphocytes Principal physiologic functions Mediators of innate immunity and inflammation (local and systemic) Adaptive immunity: regulation of lymphocyte growth and differentiation; activation of effector cells (macrophages, eosinophils, mast cells) StimuliLPS (endotoxin), bacterial peptidoglycans, viral RNA, T cell-derived cytokines (IFN-) Protein antigens Amounts produced Local or systemic effects May be high; detectable in serum BothGenerally low; usually undetectable in serum Usually local only Roles in diseaseSystemic diseases (e.g., septic shock)Local tissue injury (e.g., granulomatous inflammation) Inhibitors of synthesisCorticosteroidsCyclosporine, FK-506 qCytokine Receptors Cytokine Receptor : consist of one or more transmembrane proteins, the classification of cytokine receptors is based on structural. Cytokine receptors are divided into five families: 1) Class I cytokine receptor family (hemopoietin receptors) Binds most of the cytokines in the immune and hematopoietin systems 2) Class II cytokine receptor family 3) Immunoglobulin superfamily receptors 4) TNF receptor family 5) Chemokine receptor family Five families of Cytokine Receptor Structure 1. Type 1 cytokine receptors 1) Two Conserved pairs of cysteine residues 2) Membrane proximal WSXWS sequence 3) Unique ligand binding and others for signal- transducing chains. Among type 1 cytokine receptor , three subtype family exit: 2.Type II cytokine receptors 1)With conserved cysteins 2)Without WSXWS motif 3. Ig superfamily family. 4. TNF recptors With conserved cysteine-rich extracellular domains. 5. Seven-transmembrane helical receptors 1) Also called serpentine receptors 2) Mediate rapid and transient responses to a family of cytokines. Cytokines in Immunity qCytokines that mediate and regulate innate immunity CytokineSizePrincipal cell sourcePrincipal cell targets and biologic effects Tumor necrosis factor (TNF) 17 kD; 51-kD homotrimerMacrophages, T cellsEndothelial cells: activation (inflammation, coagulation) Neutrophils: activation Hypothalamus: fever Liver: synthesis of acute-phase proteins Muscle, fat: catabolism (cachexia)（恶恶病质质） Many cell types: apoptosis Interleukin-1 (IL-1)17 kD mature form; 33-kD precursors Macrophages, endothelial cells, some epithelial cells Endothelial cells: activation (inflammation, coagulation) Hypothalamus: fever Liver: synthesis of acute-phase proteins Chemokines (see Table 11-4) 8-12 kDMacrophages, endothelial cells, T cells, fibroblasts, platelets Leukocytes: chemotaxis, activation; migration into tissues Interleukin-12 (IL-12)Heterodimer of 35-kD + 40- kD subunits Macrophages, dendritic cellsT cells: TH1 differentiation NK cells and T cells: IFN- synthesis, increased cytolytic activity Type I IFNs (IFN-, IFN-) IFN-: 15-21 kD IFN-: 20-25 kD IFN-: macrophages IFN-: fibroblasts All cells: antiviral state, increased class I MHC expression NK cells: activation Interleukin-10 (IL-10)Homodimer of 34-40 kD; 18- kD subunits Macrophages, T cells (mainly TH2)Macrophages, dendritic cells: inhibition of IL-12 production and expression of costimulators and class II MHC molecules Interleukin-6 (IL-6)19-26 kDMacrophages, endothelial cells, T cellsLiver: synthesis of acute-phase proteins B cells: proliferation of antibody-producing cells Interleukin-15 (IL-15)13 kDMacrophages, othersNK cells: proliferation T cells: proliferation (memory CD8+ cells) Interleukin-18 (IL-18)17 kDMacrophagesNK cells and T cells: IFN- synthesis 1Tumor Necrosis Factor (TNF): 1.Definition: TNF-, a substance present in the serum of animals with bacterial endotoxin that caused the necrosis of tumors in vivo. 2.Production, Structure, Receptors Production: Product cell: mononuclear phagocytes, NK cells,mast cells. Stimulus: LPS, gram- negative bacteria which release LPS. Structure Monomer: 17kD Homotrimer: 51kD Receptor: 1. Two distinct TNF receptor: type I and type II 2. K d : 10-9 for TNF-RI and 10-10 for TNF-RII. 3. Two types of receptor are presented on all cell types. 3. Signal 1) TNF-RI : TRADD binding TRAF and RIP, leading to new gene expression 2) TNF-RI : recruitment a protein, called TNF receptor associated factors(TRAFs), TRAF then bind to FADD, leading to apoptosis. 4.Biologic Actions 1)Stimulate the recruitment of neutrophils and monocytes to sites of infection and to activate these cells to eradicate microbes. i.TNF stimulates cytokines to enhance the leukocyte recruitment. ii.TNF causes cell to express adhesion molecules to make leukocyte adhere to the endothelial cell. 4.Biologic Actions 2) In severe infections, TNF is produced in large amounts and causes systemic clinical abnormalities. i. TNF is an endogenous pyrogen. ii. TNF constitutes the acute- phase response to inflammatory stimuli. iii. TNF production causes wasting of muscle and fat cells. iv. If high quantities of TNF are produced, resulted in shock. v .TNF causes intravascular thrombosis. 2IL-1 1. Character: similar to TNF, a mediator of the host inflammatory response to infections and other inflammatory stimuli. 2. Production, Structure, Receptor Production: activated mononuclear phagocytes also : neutrophils, epithelial cells and endothelial cells Structure: IL-1 and IL-1. Receptor: type I receptor on all cell surface. type II receptor on B cell, a decoy. IL-1 Receptor Signal: IL-1 binding to IL-1 receptor leads to the activation of IRAK and ultimately NFkB and AP-1. 4. Biologic Actions 1) At low concentration, IL-1 mediate the local inflammation 2) At high concentration, IL-1 shares with TNF the ability to cause fever. 3) Doesnt induce apoptotic death. 4) Doesnt cause the pathophysiologic changes of septic shock. 5) Doesnt make tumor cell negrosis. 3Chemokines: C5a和细菌代谢产物 细胞因子（IL-8) Definition: stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues. Structure, production, Receptors Structure: according to the location of N-terminal cysteine residues. I、 CXC （）趋化因子：CXCCC II、CC （）趋化因子： CCCC III、C （）趋化因子： CC IV、CX3C （）趋化因子：CXXXCCC Production: CC and CXC: are produced by leukocytes, endothelial cells, epithelial cells and fibroblasts or T cells. Some: are induced by microbes and by inflammatory cytokines. Others: are produced constitutively without any inflammatory stimulus. Receptor: 1. At least 10 distinct receptors for CC chemokines and 6 for CXC chemokines. 2. Are expressed on leukocytes. Chemokines and receptor Biologic Actions: 1. Chemokines recruit the cells of host defense to sites of infection. T： CCR7; DC：CCR7; B： CCR7 、CXCR5; TH：CXCR5 T区HEV：CCL21; B滤泡区HEV：CXCL13 T与DC在T区作用，分化效 应细胞; TH与B在B区作用，协助Ab 产生和类别转换。 2.Regulate the lymphocytes to move to different zones. 4IL-12 Definition: a principle mediator of the early innate immune response and is a key inducer of cell-mediated immunity. Structure, production, Receptors Structure: a disulfide linked heterodimer 35-KD and 40-KD. Production: activated mononuclear phagocytes and dendritic cells. This production can be induced by helper T cells and NK cells. Receptor: Signal JAK/STAT Pathway. JAK: Janus kinases STAT: signal transducers and activators of transcription. Signal: through a JAK/STAT pathway， JAK1-STAT4. JAK/STATInvolved cytokines*Phenotype of knockout mice STAT1IFN-/, IFN-Defect in innate immunity; no reponse to IFNs STAT2IFN-/Defective immunity to viruses STAT3IL-6, IL-10Embryonic lethal STAT4IL-12Defect in TH1 development, IFN-g production STAT5aProlactinLactation defect STAT5bGrowth hormoneDwarfism STAT5a and STAT5b IL-2, IL-7, IL-9 (in addition to above) Lactation defect, dwarfism, and defective T cell proliferation in response to IL-2 STAT6IL-4Defect in TH2 development, IL-4-dependent Ig isotypes JAK1IFN-/, IFN-, cytokines using c and gp130 (e.g., IL-2, IL-4, IL-6) Perinatal lethal; defective innate immunity, possible defect in neuronal viability JAK2Epo, IL-3, IFN-Embryonic lethal, hematopoietic failure JAK3Cytokines using c chain (IL-7, IL-2, IL-4)Defect in T cell maturation Tyk2IFN-/, IFN-, IL-12, IL-10, othersDefective IL-12 response of NK cells, defective immunity to viruses Cytokines involved in JAK/STAT pathway Biologic Actions: 1.Stimulate the production of IFN-. Microbes Macrophage response IL-12 IFN-Macrophage activation Killing of microbes 2. Differentiation of CD4+ helper T cells into IFN- producing TH1 cells. 3.Enhances the CTLs. 5Type I Interferons (IFNs) Definition: the ability of these cytokines to interfere with viral infection. Structure, Production, Receptors Structure: IFN- and IFN-. IFN-, a family of 20 structurally related polypeptides, each encoded by a separate gene. IFN-, is a single protein. Production: stimulated by viral infection, specifically double- stranded RNA. IFN-, produced by mononuclear phagocytes, sometimes called leukocyte interferon. IFN-, produced by many cells, such as fibroblast, also called fibroblast interferon. Receptor: IFN- and IFN- bind to the same cell surface receptor and induce similar biologic responses. Biologic Actions 1.Inhibit viral replication. 1) 2,5 oligoadenylate synthetase 2. Increases expression of MHC I molecules. 3. Stimulates the development of Th1 cells in humans. 4. In vitro, inhibits the proliferation of many cell types. 6Interleukin-10 Definition: is an inhibitor of activated macrophages and dendritic cells. Production, Structure, Receptors Production: mainly by activated macrophages. Structure: a four-helical globular domain structure. Receptor: type II cytokine receptor. Biologic Actions: 1. IL-10 inhibits the production of IL-12 by activated macrophages and dendritic cells. 2. IL-10 inhibits the expression of costimulators and class II MHC molecules on macrophages and dendritic cells. 7Biological activity of IL-6 Biological activity of IL-15 Roles of Cytokines in Innate Immunity and Inflammation 1.For extra cellular bacteria, LPS stimulates macrophages produce TNF, IL-1, chemokines. 1)TNF, IL-1 promote stable attachment of blood neutrophils and monocytes to the infection site. 2) Chemokines stimulate leukocytes to the infection. Roles of Cytokines in Innate Immunity and Inflammation 2. For intracellular bacteria,Macrophages also secrete IL-12, which can induce the local production of IFN- from NK and T cells. 3. IL-12 also stimulates the subsequent adaptive immune response and directs it toward Th1 cells. 4. In viral infection, 4.1 Type I IFNs are secreted by infected cells and macrophages and function to inhibit viral replication. 4.2 IL-15 stimulate expansion of NK cells 4.3 IL-12 enhances the cytolytic activity of NK cells. qCytokines in Adaptive Immunity Table 11-4. Cytokines of Adaptive Immunity CytokineSize Principal cell sourcePrincipal cell targets and biologic effects Interleukin-2 (IL-2) 14-17 kDT cellsT cells: proliferation, increased cytokine synthesis; potentiates Fas-mediated apoptosis NK cells: proliferation, activation B cells: proliferation, antibody synthesis (in vitro) Interleukin-4 (IL-4) 18 kDCD4+ T cells (TH2), mast cells B cells: isotype switching to IgE T cells: TH2 differentiation, proliferation Macrophages: inhibition of IFN-mediated activation Mast cells: proliferation (in vitro) Interleukin-5 (IL-5) 45-50 kD; homodimer of 20-kD subunits CD4+ T cells (TH2) Eosinophils: activation, increased production B cells: proliferation, IgA production Interferon- (IFN-) 50 kD (glycosylated); homodimer of 21-to 24-kD subunits T cells (TH1, CD8+T cells), NK cells Macrophages: activation (increased microbicidal functions) B cells: isotype switching to opsonizing and complement-fixing IgG subclassesT cells: TH1 differentiation Various cells: increased expression of class I and class II MHC molecules, increased antigen processing and presentation to T cells Transforming growth factor- (TGF-) 25 kD; homodimer of 12.5-kD subunits T cells, macrophages, other cell types T cells: inhibition of proliferation and effector functions B cells: inhibition of proliferation; IgA production Macrophages: inhibition Lymphotoxin (LT)21-24 kD; secreted as homotrimer or associated with LT2 on the cell membrane T cells Recruitment and activation of neutrophils Lymphoid organogenesis Interleukin-13 (IL-13) 15 kDCD4+ T cells (TH2) B cells: isotype switching to IgE Epithelial cells: increased mucus production Macrophages: inhibition 一 IL-2: 1.Definition: a growth factor for antigen-stimulated T lymphocytes and is responsible for T cell clonal expansion after antigen recognition. 2.Production, Structure, Receptors Production: produced by CD4+ T lymphocytes and with peak secretion occurring about 8-12 hours after activation. Structure: Receptors : The expression of functional IL-2 receptors is enhanced. IL-2 receptor 1), , chain noncovalently associated. 2)The and chains are involved in cytokine binding, the and are involved in signal transduction. 3)IL-2R is a 55-kD poplypeptide and appears on activated T cells. 4)IL-2R is expressed at low levels on resting T cells associated with a polypeptide chain. IL-2 receptor complex binding IL-2 is changed during the process of T activation. Signal : Biologic Actions: 1.Is responsible for the proliferation of the antigen specific cells. 1. Is responsible for the proliferation of the antigen specific cells. 2.Promotes the proliferation and differentiation of other immune cells. 3. IL-2 serves to terminate immune responses by stimulating the development and function of regulatory T cells and by potentiating apoptotic death of activated T cells by Fas pathway. 二 Interleukin 4 1. Definition: is the major stimulus for the production of IgE antibodies and for the development of Th2 cells from nave CD4+ helper T cells. 2. Structure, Production, Receptors Structure: a member of the four-helical cytokine family. Production: CD4+ T lymphocyte of the Th2 subset, activated mast cells and basophiles. Receptor: 3. Signal : 4. Biologic Actions 1. Stimulate B cell Ig heavy chain class switching. 2. Stimulate the development of Th2 cells from nave CD4+ T cells and functions as an autocrine growth factor for differentiated Th2 cells. 3. Antagonizes the macrophage-activating effects of IFN-. 三 Interleukin-5: 1.Definition: is an activator of eosinophils and serves as the link between T cell activation and eosinophilic inflammation. 2. Structure, Production, Receptors Structure: is a homodimer, with each subunit containing a four- helical domain. Production: by the Th2 of CD4+ T cells and by activated mast cells. Receptors: is a type I cytokine receptor. 3.Biologic Actions: 1. Activate mature eosinophils and stimulate the growth and differentiation of eosinophils. 2. Activated eosinophils are able to kill helminths. 3. Express Fc receptor specific for IgE antibodies. 4. IL-5 stimulates the proliferation of B cells and the production of IgA antibodies. 四 Interferon- 1. Definition: 1) the principal macrophage-activating cytokines 2) serves critical functions in innate immunity and in adaptive cell-mediated immunity. 3) It has some antiviral activity,but it is not a potent antiviral inferferon. 2. Structure, Production, Receptors Structure: homodimeric p