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固有免疫 Innate immunity Qingqing Wang (王青青) Institute of immunology, ZJU [email protected] Contents • Innate immunity • Components of the innate immune system • PAMPs and PRRs • Innate immune response 2 Innate Immunity First Line of Defense Characteristics: - rapid - does not generate immunologic memory - dependent upon germline encoded receptors recognizing structures common to many pathogens 4 Characteristics of Innate and Adaptive Immunity Innate Immunity Antigen independent pattern recognition No time lag Not antigen specific No memory Adaptive Immunity Antigen dependent TCR/BCR A lag period Antigen specific Memory Functions • Innate immunity is the initial response to microbes that prevents, controls, or eliminates infection of the host by many microbes. • Innate immune mechanisms recognize the products of damaged and dead host cells and serve to eliminate these cells and to initiate the process of tissue repair. • Innate immunity to microbes stimulates adaptive immune responses and can influence the nature of the adaptive responses to make them optimally effective against different types of microbes. 6 Innate Immune System 1. Physical, chemical,microbial barriers - physical barriers include skin and mucus membranes (epithelial) - chemical barriers include stomach acidity, secreted anti-microbial peptides, defensins (防御素), cathelicidins (抗菌肽) - Normal bacterial flora 2. Cells - macrophages, neutrophils, DC, NK, B1, T, NKT… 3. Blood proteins - Complement and mediators of inflammation 4. Cytokines 7 8 Barrier Skin-mucosal barrier Physical barrier Chemical barrier Biological barrier Blood brain barrier Blood placental barrier Epithelial defense mechanisms 10 11 12 防水脂质层 板层小体:防御素和抗菌肽 Gut epithelium 表皮 Epidermis of skin 13 What happens when the physical and chemical barriers are breached? 14 Leukocyte Players of Innate Immune Responses 15 Innate-like lymphocytes(ILLs) - Unique, minor subsets of T and B lymphocytes that undergo receptor gene rearrangements to generate receptor diversity (unlike NK cells) - These subsets express limited receptor diversity, utilizing only a small number of receptor gene segments - Tend to found in specific locations in the body, usually sites that encounter exogenous antigens or pathogens 16 NK T cells Distribution bone marrow, liver, thymus, spleen, peripheral blood, lymph node NK T <1% in blood T cells; NK T in liver (mouse 30%,human 4%) NK T cells 1, cytokine: IL-4, IFN-, IL-12 2, cytotoxity perforin and FasL/Fas 3, MCP-1, MIP-1 T细胞 Surface marker:TCR、CD4-CD8-、CD8+ distribution:mucosa of skin、intestine、lung and genitals restriction:non-classical MHCⅠmolecule restriction classification:epidermis T cell systemic T cell T cells:function Anti-infection Immune surveilence Immune regulation Immune tolerance Anti-tumor B1 cells • B1 cell mainly located in abdomen cavity, thorax and intestines • B1 cell recognize LPS and capsular polysaccharide • IgM antibody • No class switch and immune memory Two types of phagocytes (1) Neutrophil granulocytes phagocytosis, intracellular killing, inflammation and tissue damage characteristic nucleus, cytoplasm granules and CD67 membrane marker. (2) Monocytes and macrophages phagocytosis, intracellular and extracellular killing, tissue repair, antigen presentation for specific immune response characteristic nucleus and CD14 membrane marker. (2)monocyte/macrophage macrophages Dendritic cells, DC • cDC myeloid DC, conventional DC • pDC (plasmacytoid DC) TLR7,9 type I interferon Complement system 30 31 Cytokines of innate immunity 32 TNF 33 IL-1 34 Innate Immune Receptors Innate immune receptors are not clonally distributed Binding of receptors results in rapid response Innate immune receptors mediate three functions: - phagocytic receptors to stimulate pathogen uptake - chemotactic receptors that guide phagocytes to site of infection - stimulate production of effector molecules and cytokines that induce innate responses and also influence downstream adaptive immune responses 35 Pathogen Recognition Most microorganisms express repeating patterns of molecular structures termed Pathogen Associated Molecular Patterns (PAMPs) Endogenous molecules that are produced by or released from damaged and dying cells are called Damage-Associated Molecular Patterns (DAMPs) Innate immune system has evolved mechanisms capable of recognizing these repeating patterns termed Pattern Recognition Receptors (PRRs) 36 37 免疫识别的危险模式理论 Danger signal Danger Theory Polly Matzinger 理论免疫学家 PAMPs DAMPs 40 Structure of bacteria pilin for DNA adhesion shape and rigidity flagellum for motion 41 Shared features of bacteria: cell walls 胞壁酸 lipopolysaccharide proteins teichoic acid proteins OM peptidoglycan peptidoglycan IM 42 Peptidoglycan 肽聚糖 teichoic acid proteins peptidoglycan N-乙酰氨基葡糖和N-乙酰胞壁酸交替的杂多糖 43 Lipopolysaccharide 脂多糖 OM peptidoglycan IM lipid 44 A类脂质A Flagellin 鞭毛 钩状体 丝状体 45 Bacterial DNA Bacteria • Frequent CG sequences • Cytosine not methylated Mammals • Rare CG sequences • Cytosine in CG is methylated 46 Viruses and double-stranded RNA • Some viruses have dsRNA genomes (rare) • Many more viruses have single-stranded RNA genomes but produce dsRNA during replication and mRNA synthesis 47 Engagement of innate immunity • Recognition of organisms based on conserved patterns – – – – – Lipopolysaccharide (gm-) Peptidoglycan (most bacteria) Flagella (many bacteria) Unmethylated CpG in DNA Single-stranded RNA (viral) 48 Pathogen Recognition Examples of Pattern Recognition Receptors (PRRs) : - Mannose-Binding Lectin (MBL) - Macrophage Mannose Receptor - Scavenger Receptors - Toll-like Receptors (TLRs) - RIG-I like Receptors (RLRs) - Nod-like Receptors (NLRs) 49 Toll-like receptors single stranded RNA TLR8 50 Toll-Like Receptors (TLRs) TNF IFN Cellular Localization: - Lysosomal localization (i.e. subcellular) of TLR-3 and TLR7,8,9 - TLR-3 and 7,8,9 recognize viral/bacterial nucleic acids - lysosomal expression isolates pathogen nucleic acid recognition away from potential cross-reaction with host mammalian nucleic acid motifs 51 52 RLRs:Retinoic Acid-Inducible Gene-I-like Receptors RD RIG-I , Retinoic Acid-Inducible Gene-1 MDA5, Melanoma Differentiation-Associated Gene 5 CARD-containing; melanoma growth-suppressive properties LGP2, Laboratory of Genetics and Physiology 2 DExH/D-box motif and a carboxy-terminal helicase domain 53 RIG-I Like Receptors (RLRs) 54 55 Nod-like receptors (NLRs) • Nucleotide-binding and oligomerization domain (NOD)-like receptors • Cytoplasmic proteins • At least 22 members • Recognize microbial components • Work synergistically with TLR MDP:胞壁酰二肽 iE-DAP:γ谷氨酰基二氨基庚二酸 56 NOD-I Like Receptors (NLRs) NLRs are cytoplasmic bacterial sensors 14 NLRPs activate IL-1β Inflammasome IPAF/NLRC4 NLRP3 NLRP1 57 Cell-associated PRRs 58 Other cell-associated PRRs 二酰基甘油酯 59 Soluble recognition and effector molecules 60 Summary and Review of Innate Immune Responses 61 Correlation between innate immunity and adaptive immunity • Initiation of adaptive immunity • Influence on type of adaptive immunity • Participate in effector phase of adaptive immunity 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”. Surface markers 1. CD56 2. CD16(FcγRⅢ) ADCC 3. FcR NK cells are generally TCR- , mIg-, CD16+, CD56+. 65 Natural killer cells • Development • Receptors • Function 66 NK receptors Activation of NK cells is the net effect of inhibitory and activating signals 67 The receptors associated with activation or inhibition 1.The receptors recognizing MHCⅠmolecules (1) Killer immunoglobulin-like receptor, KIR KIR 2DL KIR 2DS ITIM inhibitory receptor binding with DAP-12( ITAM) activating receptor KIR 3DL ITIM inhibitory receptor KIR 3DS binding with DAP-12( ITAM) activating receptor Intracellular signaling pathways coordinate inhibitory and activating signals (2) Killer lectin-like receptor, KLR CD94 NKG2A ITIM inhibitory receptor CD94 NKG2C binding with DAP-12( ITAM) activating receptor NK receptors: ‘Defense is the best offense” While both KIRs and KLRs sense the presence (absence) of MHC class I molecules, activating as well as inhibitory receptors are found in both families of receptors. - The KIRs are subdivided according to the number of immunoglobulin-like domains (2 or 3 domains) and the length of their cytoplasmic tail: Short tail = activating receptors Long tail = inhibitory receptors - The KLR are heterodimers of CD94 associated with a NKG2 molecule. Six distinct NKG2 isoforms exist in humans. NKG2C/CD94 = activating receptor NKG2A/CD94 = inhibitory receptor NKG2B/CD94 = inhibitory receptor NKG2D homodimer = activating receptor. 71 (3) The significance of KIR and KLR NK cells are prevented from killing host cells because they recognize the host classⅠMHC molecules. Thus, they only attack cells whose classⅠMHC molecules are lost or altered, as occurs frequently in malignancy or viral infection. 2. The receptors recognizing non-MHCⅠ molecules (1) NKG2D binding with DAP-10 ( ITAM) activating receptor ligand: MⅠC A/B (on some tumor cells) (2) natural cytotoxicity receptor, NCR NKp46,NKp30 binding with CD3( ) NKp44 expressed on activated NK cells binding with DAP-12 ( ITAM) activating receptor 74 Functions of NK cells 1. Anti-infection provide an early innate barrier to infection by eliminating infected host cells 2. Anti-tumor kill tumor cells directly: perforin, granzymes, ADCC 3. Immunoregulation Activated NK cells produce cytokines such as IFN-, TNF-, G-CSF. These cytokines can activate T cells. Functions 76 Release of cytotoxic granules at the site of contact with infected cells NK cell Target cell - First contact between a CTL or NK cell with infected cells is via non-specific binding of adhesion molecules (LFA-1 (blue) on T and NK cells with ICAM-1 or ICAM-2 (brown) on target cells). This makes a channel between the target and the cytotoxic cell. - Specific antigen/MHC class I recognition by TCR on CTL, or engagement of the NK’s natural cytotoxic receptors (NCR) (green) by non-MHC ligands (orange) on the surface of the target cell. This results in a polarization of the cell: the actin cytoskeleton (green staining in the immunofluorescence microscopy) at the site of contact is reorganized as to aligning the microtubule-organizing center (MTOC), as well as the secretory apparatus, including the Golgi (GA). The GA-derived lytic granules (stained in red in the photomicrograph) are specifically directed onto the target cell. - The content of the granules is directly released onto the target cell. Why are NK cells prominent tumor killers? Similar to many pathogens, tumor cells can escape the adaptive immune system, by downregulating the expression of MHC class I. This makes them more susceptible to NK cells. - The regression of transplanted tumors in a normal mouse model (blue line) is largely due to the action of CTLs recognizing tumor antigens presented on MHC class I (right panel). Albeit the presence of NK cells, this regression is absent in nude mice (red line) in which CTLs do not develop. -Tumor variants that express low levels of MHC class I become susceptible to NK cells, especially in nude mice (have higher levels of NK cells than wild type mice). Thus tumors that are sensitive to NK killing grow less well in nude than normal mice (central panel). - Transfection of MHC class I genes resulting in high expression of this protein restores NK cell resistance but susceptibility to CTL in normal mice (left panel; blue line). Thanks for your attention! If you have any questions, please feel free to contact me: [email protected]