中科院细胞与分子免疫学课程Chapter11

Section IV Effector Mechanisms of Immune Responses,Chapter 11 Cytokines,Nomenclature:,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:,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,AutocrineCytokine binds to receptor on cell that secreted it.,ParacrineCytokine binds to receptors on near by cells,EndocrineCytokine binds cells in distant parts of the body,3 Cytokine Actions,PleiotropyAct on more than one cell type,RedundancyMore than one cytokine can do the same thing (IL-2, IL-4,IL-5),SynergyTwo 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-g and TNF),AntagonismTwo or more cytokines work against each other (IL-10 and IFN-g),4. Cytokines make functions in binding to receptorKd: 10-10-10-125.External signals regulate the expression of cytokine receptor.6. Cytokines can change the gene expression in target cells.,Functional Classification of Cytokine,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,Cytokine 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 systems2) Class II cytokine receptor family3) Immunoglobulin superfamily receptors4) TNF receptor family5) Chemokine receptor family,Five families of Cytokine Receptor Structure,1. Type 1 cytokine receptors,Two Conserved pairs of cysteine residuesMembrane proximal WSXWS sequenceUnique ligand binding and others for signal-transducing chains.,Among type 1 cytokine receptor , three subtype family exit:,2.Type II cytokine receptors,With conserved cysteinsWithout WSXWS motif,3. Ig superfamily family.,4. TNF recptors,With conserved cysteine-rich extracellular domains.,5. Seven-transmembrane a helical receptors,Also called serpentine receptorsMediate rapid and transient responses to a family of cytokines.,Cytokines in Immunity,Cytokines that mediate and regulate innate immunity,Tumor Necrosis Factor (TNF):1.Definition: TNF-a, 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: 17kDHomotrimer: 51kD,Receptor:,Two distinct TNF receptor: type I and type IIK d : 10-9 for TNF-RI and 10-10 for TNF-RII.Two types of receptor are presented on all cell types.,3. Signal,1) TNF-RI : TRADD binding TRAF and RIP, leading to new gene expression2) TNF-RI : recruitment a protein, called TNF receptor associated factors(TRAFs), TRAF then bind to FADD, leading to apoptosis.,4.Biologic Actions,Stimulate the recruitment of neutrophils and monocytes to sites of infection and to activate these cells to eradicate microbes.TNF stimulates cytokines to enhance the leukocyte recruitment.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.,IL-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-1a and IL-1b. 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 inflammation2) 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.,Chemokines:,Definition: stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues.,Structure, production, ReceptorsStructure: according to the location of N-terminal cysteine residues.,I、 CXC （）趋化因子：CXCCCII、CC （）趋化因子： CCCCIII、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:,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：CXCR5T区HEV：CCL21;B滤泡区HEV：CXCL13T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.,IL-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 kinasesSTAT: signal transducers and activators of transcription.,Signal: through a JAK/STAT pathway， JAK1-STAT4.,Cytokines involved in JAK/STAT pathway,Biologic Actions:,Stimulate the production of IFN-g. Microbes,Macrophage response,IL-12,IFN-g,Macrophage activation,Killing of microbes,2. Differentiation of CD4+ helper T cells into IFN-g producing TH1 cells.3.Enhances the CTLs.,Type I Interferons (IFNs),Definition: the ability of these cytokines to interfere with viral infection.,Structure, Production, Receptors,Structure: IFN-a and IFN-b.IFN-a, a family of 20 structurally related polypeptides, each encoded by a separate gene.IFN-b, is a single protein.Production: stimulated by viral infection, specifically double-stranded RNA. IFN-a, produced by mononuclear phagocytes, sometimes called leukocyte interferon. IFN-b, produced by many cells, such as fibroblast, also called fibroblast interferon.,Receptor: IFN-a and IFN-b bind to the same cell surface receptor and induce similar biologic responses.,Biologic Actions,Inhibit viral replication. 1) 2,5 oligoadenylate synthetase2. 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.,Interleukin-10,Definition: is an inhibitor of activated macrophages and dendritic cells.,Production, Structure, Receptors,Production: mainly by activated macrophages.Structure: a four-a-helical globular domain structure.,Receptor: type II cytokine receptor.,Biologic Actions:IL-10 inhibits the production of IL-12 by activated macrophages and dendritic cells.IL-10 inhibits the expression of costimulators and class II MHC molecules on macrophages and dendritic cells.,Biological activity of IL-6,Biological activity of IL-15,Roles of Cytokines in Innate Immunity and Inflammation,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-g 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 cells4.3 IL-12 enhances the cytolytic activity of NK cells.,Cytokines in Adaptive Immunity,Table 11-4. Cytokines of Adaptive Immunity,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,a, b,g chain noncovalently associated.The a and b chains are involved in cytokine binding, the b and g are involved in signal transduction.IL-2Ra is a 55-kD poplypeptide and appears on activated T cells.IL-2Rb is expressed at low levels on resting T cells associated with a polypeptide g chain.,IL-2 receptor complex binding IL-2 is changed during the process of T activation.,Signal :,Biologic Actions:,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 41. 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-ahelical 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-g.,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, ReceptorsStructure: is a homodimer, with each subunit containing a four-a- 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:,Activate mature eosinophils and stimulate the growth and differentiation of eosinophils.Activated eosinophils are able to kill helminths.Express Fc receptor specific for IgE antibodies.IL-5 stimulates the proliferation of B cells and the production of IgA antibodies.,四 Interferon-g,1. Definition: the principal macrophage-activating cytokines serves critical functions in innate immunity and in adaptive cell-mediated immunity. It has some antiviral activity,but it is not a potent antiviral inferferon.2. Structure, Production, ReceptorsStructure: homodimeric protein Production: produced by NK cells, CD4+ Th1 cells and CD8+ T cells and is the signature cytokines of the Th1 subset of helper T cells.,In innate immunity: NK cells secrete IFN-g in response to recognition of unknown components of microbes or in response to IL-2. In adaptive immunity:T cells produce IFN-g in differentiation of T cell.,Receptor:,3. Signal:,JAK-STAT signal, STAT1 was activated and stimulate IFN-g-responsive genes.MHC molecules and B7 costimulators were encoded.,4. Biolog