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Innate immunity
- 1. INNATE IMMUNITY Addah de Peralta 1st year Fellow Section of Allergy and Immunology
- 2. OUTLINE • Overview of the Innate Immunity • Recognition of Microbes and Damaged Self by Innate Immune System • Cell-Associated Pattern Recognition Receptors and Sensors of Innate Immunity • Cellular Components of the Innate Immune System • Soluble effector molecules of the Innate Immunity • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 3. Overview of the Innate Immunity Innate Immunity • Always present, ready to combat • Provide early defense Major Components • Surface epithelia • Tissue sentinel cells • White blood cells • Plasma proteins • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 4. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 5. Evolution of Innate Immunity • The oldest part of the immune system • Appeared very early in evolution • When first multicellular organism evolved (~750 million years ago) • Toll like receptors • Found in every life form in the evolutionary tree • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 6. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 7. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 8. Recognition of Microbes and Damaged Self by Innate Immune System • PAMPS (Pathogen –Associated Molecule pattern) • DAMPS (Damage-associated molecular patterns) • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 9. 9 Innate immunity The innate immunity is our first line of defense, and relies on cellular and humoral mechanisms to actively match the invading pathogens as fast as possible. Its main targets are microbes and cells infected by microbes. The outcome of innate immunity is INFLAMMATION and activation of the ANTIVIRAL STATE. Recognition of microbes and infected cells occurs via: SIGNALS Damage-Associated Molecular Patterns (DAMP) Damaged/ Infected cells RECEPTORS Pathogen-Associated Molecular Patterns (PAMP) Microbes TLRs, RIGs, NOD, Mannose receptor, Dectins, Scavenger receptors Phagocytes Antibodies, complement system, antimicrobial peptides Mucosae and circulating • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 10. Recognition of Microbes and Damaged Self by Innate Immune System PAMPS (Pathogen –Associated Molecule pattern) • Structures produced by microorganisms which are recognized by and stimulate the innate immune system DAMPS (Damage-associated molecular patterns) • Endogenous molecules that are produced or released from damaged and dying cells that bind to Pattern recognition receptor stimulation of innate immune response • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 11. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 12. 12 Innate immunity – PAMPs and DAMPs PAMPs Microbes Nucleic Acids ssRNA Viruses dsRNA Viruses Non-meth. CpG Viruses, Bacteria Proteins Pilin Bacteria Flagellin Bacteria Wall lipids LPS Gram- bacteria LTA Gram+ bacteria Carbohydrates Mannans Fungi Glucans Fungi, Bacteria DAMPs Stress proteins HSP Crystals Monosodium urate Nuclear proteins HMGB1 All of these molecules are necessary for the normal functions and survival of microbes.Their recognition ensures wide coverage and a strong interference on microbial life cycle. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 13. DAMPs Damage-associated molecular patterns • Endogenous molecules that are produced or released from damaged and dying cells that bind to Pattern recognition receptor stimulation of innate immune response • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 14. Cell-Associated Pattern Recognition Receptors and Sensors of Innate Immunity • Toll like Receptors • Cystosolic Receptor for PAMPs and DAMPs • NOD-Like Receptors: NOD1 and NOD2 • Cystosolic DNA Sensors and the STING Pathway • RIG-Like Receptors • Inflammasomes • Other Cell-Associated Pattern Recognition Receptors • C-Type Lectin Receptors for Microbial Carbohydrates • Scavenger Receptors • Formyl-Peptide Receptors • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 15. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 16. Pattern recognition receptors • Structure: several families of protein • Location: expressed on many effector cells • 2 locations: 1. Transmembrane 2. Cystosolic
- 17. Pattern recognition receptors • Signaling receptors of the innate immunity that recognize PAMPs and DAMPS activation of the innate immune system • Binding to PAMPs and DAMPs activation of signal transduction promotion of antimicrobial and pro-inflammatory functions of the cells • Responsible for facilitating clearance of microbes from blood and ECF by enhancing uptake into phagocytes or activating extracellular killing mechanism • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 19. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 21. Toll like receptors • 9 different functional TLRs in humans (TLR 1-9) • Mammalian TLR are involved in responses to a wide variety of molecules that are expressed by microbes (but not by healthy mammalian cells) • Found in the cell surface and intracellular membranes • Thus are able to recognize microbes in different locations
- 22. Toll like receptors • Type 1 integral membrane glycoproteins • Contain leucine-rich repeats flanked by characteristic cysteine-rich motif in their extracellular region (involved in ligand binding) • Toll /Il-1 receptor (TIR) domain in cytoplasmic tails (essential for signaling) • Also found in the cytoplasmic tails of the receptor for cytokines IL-1 and IL-
- 23. Toll-like receptors (TLRs) • They exist as membrane-bound and cytosolic form • Show the widest ability to recognize PAMPs. They also recognize DAMPs • In humans 9 TLRs are known (TLR 1-9). Abbas et al. • TLR 1,2,4,5,6 • Plasma membrane • TLR 3,7,8,9 • Inside the cell (endoplasmic reticulum and endosomal membrane) Bacterial products that bind to TLR
- 24. Toll like receptors • Involved in responses to endogenous molecules whose expression or location indicates cell damage • Heat shock protein (HSP) and high-mobility group box 1 (HMGB1) are intracellular becomes extracellular when released from injured or dying cell • From extracellular region activate via TLR2 & TLR4 signaling in Dendritic ells, macrophage and other cell types • Structural basis • Resides on the multiple extracellular leucine rich modules of these receptors (that bind directly to PAMPs or adaptor molecules that bind to PAMPs)
- 25. Signaling Pathways of TLRs Products of the pathway are important for: • Inflammation • Anti-viral response • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 26. Pattern recognition receptors • Structure: several families of protein • Location: expressed on many effector cells • 2 locations: 1. Transmembrane 2. Cystosolic
- 27. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 28. Cystosolic Receptors NOD-like receptors (NLRs) • cytosolic receptors for PAMPs and DAMPs • More than 20 NLRs are known, but the best characterized are NOD1 and NOD2 • NOD1 and NOD2 are especially important against Helicobacter pylori • NOD1 • recognizes preferentially bacterial peptidoglycans • NOD2 • recognizes muramyl dipeptide from Gram+ and Gram- bacteria. • defects in NOD2 might be involved in Chron’s disease. • NLRs activation leads to gene activation in a similar way to TLRs. and • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 30. Cystosolic Receptors RIG-like receptors (RLRs) • cytosolic receptors for viral RNA (both ssRNA and dsRNA). • Best characterized RLRs are RIG-I and MDA5, which recognize different viral nucleic acids. • Once activated, they will lead to transcription of Type-I interferons and antiviral defenses activation. • These include suppression of transcription factors needed for viral genes (like EIF2a), the synthesis of RNAse which degrade viral RNA and suppression of viral proteins assembly complexes. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 31. Cystosolic Receptors Cystosolic DNA sensors • Molecules that detect microbial double-stranded (ds)DNA in the cytosol activates signaling pathway initiation of antimicrobial response STING pathway (stimulator of IFN genes) • An important mechanismof dsDNA-induced activation of type-1 interferon responses • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 32. The STING cystosolic DNA sensing pathway
- 33. Cystosolic Receptors Inflammasone • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 34. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 35. Other Cell-Associated Pattern Recognition Receptor • C-Type Lectin Receptors for Microbial Carbohydrates • Scavenger Receptors • Formyl-Peptide Receptors • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 36. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 38. C-Type Lectin Receptors • Microbial carbohydrates are recognized by calcium-dependent Lectins (C-type Lectins). These include: • Mannose receptor (CD206), which recognizes D-mannose, L-fucose and N-acetyl-D-glucosamine. • Dectins, which recognize fungal b-glucan (dectin-1) and mannose- rich oligosaccharides (dectin-2). • Langherin (CD207), DC-SIGN, and others
- 41. N-FMLP receptors • N-FMLP receptors (like FPR and FPRL1) • Those receptors bind to n-formylmethionine leucyl-phenylalanine, a sequence which characterizes all bacterial proteins but not human ones (apart from mitochondrial proteins).
- 42. Cellular Components of the Innate Immune System • Epithelial Barriers • Phagocytes • Dendritic Cells • Cytokine –Producing Innate Lymphoid Cells • Natural Killer Cells • Mast Cell • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 43. Abbas et al. Epithelia: - Physical barrier - Defensive molecules Circulating defenses: - Natural antibodies - The Complement system Cellular defenses: - Phagocytes - NK cells • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 44. Epithelia play a big role in the very first match with invading pathogens. As most of the microbes enter the body via the skin, the respiratory and the gastrointestinal tract, these epithelia evolved specific strategies to counteract pathogens, like: • Expression of sialomucins on the external side of the plasma membrane, which electrostatically repel bacterial walls • Production of antimicrobial peptides (like defensins and cathelicidins), which both directly attack the microbes and help their recognition by innate immunity cells • Hosting of intraepithelial lymphocytes. While some of them are “classical” ab T-cells, many are gd T-cells, which are particularly good at recognizing bacterial phospholipids. They can directly attack microbes and stimulate phagocyte responses.
- 45. Abbas et al. Epithelia: - Physical barrier - Defensive molecules Circulating defenses: - Natural antibodies - The Complement system Cellular defenses: - Phagocytes - NK cells • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 46. Phagocytes • Cells that have specialized phagocytic function, primarily macrophages and neutrophils are the first line of defense against microbes that breach the epithelial barrier
- 48. Dendritic Cells • Rapidly and efficiently detect invading microbes because of: • their location in the tissue • Expression of numerous PRR fro PAMPs and DAMPs
- 49. Cytokine-Producing Innate Lymphoid Cells • 3 subsets of innate lymphoid cells called: • ILC1,ILC2 and ILC3 • Produce different cytokines • Express different transcription factors, analogous to Th1, Th2 and Th17 of CD4 T lymphocytes subset
- 50. Natural Killer Cells Effector function of NK cells are to : • Kill infected cells • Produce IFN-γ, which activates macrophages to destroy phagocytosed microbes • First known ILC • Cytotoxic cells that play important roles in innate immune response • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 51. Functions of activating and inhibitory receptors of NK cells
- 52. Structure and ligands of activating and inhibitory receptors of NK Cells • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 53. Soluble Effector Molecules of Innate Immunity • The Complement System • Pentraxims • Collectins and Ficolins • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 54. Abbas et al. Epithelia: - Physical barrier - Defensive molecules Circulating defenses: - Natural antibodies - The Complement system Cellular defenses: - Phagocytes - NK cells • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 55. The complement system is a network of many (> 20) soluble and membrane- bound proteins which are normally present in the blood flow in the form of inactive precursors (pro-enzymes). The term complement (C) was used to refer to a heat-instable serum component which was able to lyse bacteria when incubated at 37oC, but lost when incubated at 56oC for 30 minutes (antibodies are thermo stable!). • The complement system is activated by microbial macromolecules or by antibodies bound to them. There are 3 complement activation pathways. • Complement activation proceeds through sequential cleavage and activation of circulating inactive forms of C proteins. Once cleaved, those precursors become active and acquire proteolytic activity. Jules Bordet
- 56. The Complement System • The final stages of complement activation lead to formation of MAC (Membrane Attack Complex), which is a canal (similar to acquaporins) structure allowing water to enter into the microbes and kill them by osmotic lysis. • Microbes bound to complement fragments can be more-easily recognized and killed by phagocytes • Self cells, but not microbes, express proteins which inhibit complement activation. Jules Bordet
- 57. Pathway of Complement Activation
- 58. C3 has a spontaneous cleavage turnover in body fluids, so it can directly recognize microbes. The classical and lectins pathway provide specificity to complement activation Abbas et al.
- 59. Pentraxins • Pentraxins • A family of plasma proteins that contain 5 identical globular subuntis • Includes acute phase reactant, CRP • ↑ CRP is a result of increased synthesis by the liver induced by IL-6 and IL-1 • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 60. Collectin and Ficolin • Collectin • Family of trimeric or hexameric proteins • Contains a collagen-like tail connected by a neck region to a calcium-dependent (C-type) lectin head • 3 members that are soluble effectors of the innate immunity 1. MBL (Mannose binding protein) 2. Surfactant Protein A (SP-A) 3. Surfactant Protein D(SP-D) • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 61. Collectin and Ficolin • Ficolins • Plasma proteins that are structurally similar to collectins • Possess a collagen-like domain that have a fibrinogen-type carbohydrate recognition domain (instead of a C-type lectin) • Bind to several species of bacteria, opsonizing them and activating complement in a manner similar to MBL • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 63. Inflammatory Response • The Major Proinflammatory Cytokines of Innate Immunity • Tumor Necrosis Factor • Interleukin -1 • Interleukin 6 • Other Cytokines • Recruitment of Leukocytes to the Sites of Infection • Ingestion and Killing of Microbes by Activated Phagocytes • Systemic and Pathologic Consequences of Inflammation
- 64. Acute inflammation • Principal way by which innate immune system deals with infection and tissue injury • There is an accumulation of leukocytes, plasma proteins and fluid derived from blood at an extravascular tissue site of infection or injury • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 65. General properties • Produced mainly by tissue macrophage and dendritic cells • Most cytokines act on cells close to their cell of origin (paracrine action) • Cytokines produced: TNF, IL-17, IL-5, IFN-γ • Role of cytokines of innate immunity • Induces inflammation • Inhibits viral replication • Promotes T cell response • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 67. General properties THREE MOST IMPORTANT PRO-INFLAMMATORY CYTOKINES OF THE INNATE IMMUNITY 1. Tumor Necrosis Factor 2. IL-1 3. IL-6 • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 69. Interleukin-1
- 70. Interleukin-6
- 73. Local and systemic actions of cytokines in inflammation
- 74. Phagocytosis and Intracellular destruction of microbes
- 75. Systemic and Pathologic consequence of inflammation • TNF, IL-1 and IL-6 • Are produced during the innate immune response to infection or tissue damage • TNF and IL-1 • Act on hypothalamus to induce an increase in temperature • IL-1 and IL-6 • Induce hepatocytes to produce acute phase reactant • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 77. The Anti-Viral Response • The major way by which the innate immune system blocks viral infection is to induce the expression of Type 1 interferon • Type 1 interferon • Large family of structurally related cytokines that mediate the early innate immune response to viral infections • Most important action is to inhibit viral replication • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 78. • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 79. Stimulation of Adaptive Immunity Innate immunity • Provides signals that function in concert with antigen to stimulate the proliferation and differentiation of antigen-specific T and B lymphocytes • Two signal hypothesis • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 80. Two signal hypothesis • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 81. Mechanisms that limit Innate Immunity • Regulated by a variety of inhibitory mechanisms that limit potential damage to tissues • IL-10 • Cytokine that is produced by and inhibits the activation of macrophages and dendritic cells • Excellent example of a negative feedback regulator • Produced by nonlymphoid cell types and regulatory T cells • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 82. Mechanisms that limit Innate Immunity IL-1 receptor antagonist (IL-IRA) • Natural antagonist of IL-1 that is structurally homologous to the cytokine • Competitive inhibitor of IL-1 Autophagy genes • Products regulate the secretion of inflammatory cytokines • Overview • PAMPS & DAMPs • PRR • Cellular Components • Soluble effector • Inflammatory Response • Antiviral response • Stimulation of Adaptive Immunity • Mechanism that limit Innate Immune responses
- 83. THANK YOU
Editor's Notes
- TLRs are express on the cell surface and others in endosomes (it may form a homodimer or heterodimers TLR
- FIGURE 4-3 Signaling pathways and functions of TLRs. TLRs 1, 2, 5, and 6 use the adaptor protein MyD88 and activate the transcription factors NF-κB and AP-1. TLR3 uses the adaptor protein TRIF and activates the IRF3 and IRF7 transcription factors. TLR4 can activate both pathways. TLRs 7 and 9 in the endosome use MyD88 and activate both NF- κB and IRF7.
- Other microbial PAMPs are recognized by: Scavenger receptors (like SR-A and CD36). Initially identified as receptors for oxidized LDL (involved in atherosclerosis), they bind to bacterial polyanions (LPS, LTA, nucleic acids etc.).
- Nk cells recognize ligands on infected cells or cells undergoing other types of stress and kill cells Nk cells respond to IL-12 produced by macrophage to kill phagocytosed microbes
- Nk cells distinguish infected and stressed cells from healthy cells and NK cell function is regulated by a balance between signals that are generated from activating receptors and inhibitory receptors
- Steps: Type 1 interferon, signaling thru the Type 1 interferon receptor activate several genes that confer resistance to viral infection called an ANTIVIRAL STATE Type 1 interferon are produced by virus-infected cell in response to TLR signaling Type 1 interferon binds to receptor of unifected cells Activate the JAK-STAT signaling pathway induces the expression of genes whose products interfere with viral replication Type 1 interferon also binds to receptors of infected cells and induce expression of genes whose products enhance the cell’s susceptibility to CTL mediated killing
- Antigen recognition by lymphocytes provides signal #1 for activation of lymphocytes Molecules induced by inate response provides signal #1