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Chapter 2

Innate Immunity

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Three Defense Categories

• Physical barriers• Fixed or ‘hard-wired’ mechanisms (innate)• Adaptive immune response

– “” vaccination– long-term protection

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Physical Barriers Innate immunity

• Outer epithelial – Physical barrier– Colonization by nonpathogenic resident microorganisms

• Competition for the bad pathogens to move in • What if a pathogen does move in?

– Innate immune response quickly takes action to eliminate the bug

– Therefore consider this:

physical barrier = “fixed defenses”+ innate immunity

- Completely determined by genes inherited and ready at all times

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Are the defenses of the innate immune response easy to assess?

• Aren’t most infections eliminated prior to development of symptoms?

• Maybe you don’t even have to see a doctor• Conclusion = innate immunity is very effective

– After all we do have vast populations of resident microbes and most the time we are well

• Innate response very effective and important!– Rare inheritable innate immune mechanism defects

• = substantial protection reduction!

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Let’s look at the benefits of innate and adaptive immunity

• 1 infection time course Normal individual = infection is cleared by combined effects of innate and adaptive immunity

• Lack of innate immunity = uncontrolled infections, i.e. adaptive immune response cannot be deployed

• Lack of adaptive immunity = infection is initially controlled by innate immunity, but cannot be cleared from the body

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Infectious diseases are caused by pathogens of diverse types that live and

replicate in the human body

• 4 Human pathogen types– Viruses, bacteria and fungi– Parasites

• Unicellular protozoa • Multi-cellular worms

• Pathogens are diverse in their– Structure– Manner of exploiting the human body– Type of damage to tissue

• Tissue damage and disease symptoms can be caused– Directly– Indirectly

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Pathogens damage tissue in different ways

1. Release exotoxins 2. Phagocytes degrade microbe, endotoxins released

cytokines3. Infected cells killed /damaged

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Different components of the immune system contribute to immunity against different types

of microbes in different locations• Some pathogens, all stages are extracellular

– accessible to soluble components of the immune system.• Others, exploit intracellular sites to grow and replicate

– not able to use soluble components.

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Extracellular vs. intracellular infections can be further subdivided

• Different sites affect the type of immune mechanism used to eliminate the pathogen

• Extracellular are accessible to soluble immune system molecules

• Intracellular forms are not accessible to soluble immune system molecules– Intracellular pathogens in nucleus or cytosol attacked by killing the

infected host cell• Interferes with the pathogen’s life cycle• Exposes the released pathogens from the killed cells to soluble

immune system molecules– Intracellular pathogens in vesicles

• Activate the infected cell to intensify its antimicrobial activity• Almost all viruses, bacteria, fungi or parasites are at some time in

the extracellular system Abs

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Most pathogens infect only a few related host species

• Therefore humans are infrequently infected via another vertebrate species– Most of time infection is via directly or indirectly by another person– Parasites may require an intermediate passage through distantly

related organism• WHY?• To complete it’s life cycle

• Pathogen’s ability to persist outside of the body varies– Determines the ease with which a particular disease is spread

• Anthrax = spores = resistant to heat/desiccation• HIV sensitive to environment change therefore requires intimate

contact or exchange of infected body fluids

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The Pathways

• C3 is by far the most important molecule in the complement cascade.

• The biggest difference in the different pathways is how they are activated.

• 1) The quickest of the 3 complement pathways is the alternative pathway– It starts depositing C3b on the surface of the pathogen at the

beginning of infection.• 2) The lectin pathway can begin as soon as an infection is

realized but takes a little time to become effective.• 3) The Classical pathway is part of both the innate and

adaptive immune response and can be activated by C-reactive protein (innate) or antibody (adaptive) binding to the pathogen.

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Complement Fixation

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Complement activation by the alternative pathway tags microorganisms for destruction

• 1st immune system components to be activated = complement – Ubiquitous in blood and lymph– Soluble proteases that circulate in an inactive form called

zymogens– A molecular defense that can be utilized immediately

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The Thioester Bond

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1st Step in the alternative pathway involves spontaneous hydrolysis and

activation of complement component C3

• This process occurs continuously at low rate in blood, lymph and extracellular fluids

• Rate increases in vicinity of certain pathogens• iC3 is the product of C3 hydrolysis• iC3 binds to factor B in the blood or ECF making

factor B susceptible to cleavage by factor D• at pathogen’s surface• iC3Bb is produced (soluble form of C3 convertase)• iC3Bb cleaves C3 into C3a and C3b• Some of C3b becomes bound to pathogen’s

surface

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Thioester bond

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C3 convertase of the alternative pathway

• Factor B binds to C3b fragments and is cleaved by factor D, the complex of C3bBb is formed on the pathogen‘s surface = C3 convertase of the alternative pathway

• Assembly of some C3 convertase molecules results in more C3 being cleaved and more C3b attached to the pathogen’s surface assembly of even more convertase…process of progressive amplification that rapidly coats the pathogen with C3b

• High density C3b fragments on the pathogen surface form effective ligands for complement receptors (CR1) of macrophages in infected tissue

• Covalently coupled C3b fragments tag the pathogen for destruction by phagocytosis

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C3b Tags Pathogens for Phagocytosis

• Opsonin – a protein bound to the surface of a pathogen that facilitates its phagocytosis.

• CR1 – Complement Receptor 1 – bind to C3b deposited on microbial surfaces phagocytosis– Also plays a protective roll on human cell surfaces by disrupting C3

convertase.

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How is the sequence of complement-activating reactions continued?

• Binding of C3b to existing C3bBb complexes at pathogens surface forms the alternative C5 convertase = C3b2Bb (C4b2a3b in classical pathway)– Activates C5 terminal components of complement

(C6-C9)• Pores transmembrane channels pathogen lysis

– C5a recruits neutrophils to infection site• Most potent anaphylatoxin

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What about protecting the host cell?Regulatory Proteins

• Proteins controlling complement activation– Ensure C3b is densely deposited on microbial surfaces;

not on the surfaces of human cells• Plasma protein = properdin (factor P)

• Factor P binds to C3 convertase (C3bBb) on microbial surfaces and protects it from inhibition by factor H– Factor H plasma protein reduces complement reactions

by making C3b susceptible to cleavage by factor I– On human cells the complement pathway is stopped by

human cell-surface proteins decay-accelerating factor (DAF) and membrane co-factor protein (MCP).

– DAF and MCP control proteins destroy C3 convertase activity by binding to C3b and displaces Bb and/or renders C3b susceptible to cleaved by factor I

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What about protecting the host cell?Regulatory Proteins

• When C3bBb is formed on a human cell surface it is rapidly disrupted by the action of one of two membrane proteins: decay accelerating factor (DAF) or membrane cofactor protein (MCP)

• These regulatory proteins ensure that much complement is fixed to pathogen surface and little is fixed to human cell surfaces

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Complement activation limits bacterial infections…but some bacteria mimic human

cells to evade the actions of complement

• Ex. Streptococcus pyogenes and Staphylococcus aureus

• C3b bound on these pathogen’s surfaces is readily inactivated by factor H

• Abs coat the bacterial surface and mask sialic acids before complement is bound therefore these bacterial are only resistant to the effects of complement when no specific antibacterial antibody is present

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Inflammation

• C3a and C5a contribute to acute inflammation– Also referred to as anaphylatoxins– C5a is more stable and potent than C3a

• What exactly do they do?– bind mast cells, phagocytes and endothelial cells release of histamine

• Histamine increases blood vessel permeability and blood flow• Activate endothelial cells direct phagocytes to site of infection

• C5a Increases the adherence of monocytes and neutrophils to blood vessel walls and acts as a powerful chemotactic factor

• What’s this mean?– C5a is able to attract phagocytes to areas where complement has

been fixed. – The leukocytes follow a gradient of the C5a back to the site of

infection.

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Several classes of plasma protein limit the spread of infection

• Protease inhibitors such as2-macroglobulin inhibit potentially damaging proteases

• Microbe invasion and colonization of human tissues is dependent on microbial proteases

• In response human plasma is loaded with protease inhibitors -macroglobulins first trap the protease with a “bait”

region • protease cleaves the bait -macroglobulin binds

covalently through activation of thioester group • surrounds the protease (still active) but cannot access

other protein substrates

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Serpins and -macroglobulin inhibit potentially damaging proteases

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Antimicrobial Peptides - Defensins

• Two types of defensins - -defensins and -defensins.

• Amphipathic (both hydrophobic and hydorphilic) regions.

• Penetrates the microbial membrane and disrupts it. -defensins

– Produced mainly by neutrophils and Paneth cells (specialized epithelial cells of the small intestine)

-defensins– Expressed mainly by epithelial cells of the respiratory

tract the urogenital tract and the skin.

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Phagocytosis by macrophages provides a first line of cellular defense against

invading microorganisms

• Pathogen invades 1st effector cells (resident macrophages)– Resident in tissues– Prevalent in connective tissues

• Linings of GI, respiratory tract, lung alveoli, liver– Long-lived phagocytic cells– Involved in both innate and adaptive immunity

• Enhance phagocytosis more efficient using macrophage surface receptors

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Enhance phagocytosis more efficient using macrophage surface receptors

• C3b is ligand for Macrophage CR1• Pathogen C3b surface fragments + degraded by

factor I iC3b now a ligand for macrophages CR3 and CR4 receptors

• Combination of opsonization by complement and phagocytosis by macrophages– Pathogens recognized and destroyed at beginning of

infection

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Phagocytosis by macrophages is aided by receptors of innate immunity that bind directly

to microbial surface componentsPhagocytic Receptors

• Surface components are characteristic of pathogens– But absent from human cells

• CR3 and CR4 recognize iC3b and other ligands such as:– LPS, lipopolysaccharide (Gram negative bacteria)– Lipophosphoglycan– Filamentous hemagglutinin– Cell-surface structures on yeast

• Carbohydrate-binding proteins = lectins– Bind to particular carbohydrates (not found on human cells)– Mannose and glucan receptors are examples

• Scavenger receptors = preference for molecules that are negatively charged.

– Nucleic acids and phosphate-containing lipoteichoic acids (Gram positive bacteria)

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Macrophages have several types of surface

receptor that bind to constituents of microbial

surfaces and promote phagocytosis

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Binding of Microbe to Phagocytic Receptors Initiates the Phagocytosis

• Binding of the phagocytic receptors initiates receptor mediated endocytosis (phagocytosis).

• The microbe is enveloped into a vesicle (phagosome)

• The phagosome is joined to a lysosome • The lysosome contains degradative enzymes and

toxic substances to destroy the pathogen.

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Receptors that detect microbial products signal macrophage activation and cytokine

secretion

• Macrophage have receptors or sensors for pathogen components that signal macrophage to make and secrete cytokines– Toll-like receptors (TLR)

• 10 receptors• Specificities for different microbial products• TLR-4 senses ligand LPS

– TLR-4 expressed on Macrophages– TLR-4 detects LPS and sends a signal to the nucleus of the

macrophage to make and secrete inflammatory cytokines as well as cytokines that activate innate immune responses

– LPS is a major gram-negative bacteria component– LPS is an endotoxin responsible for septic shock

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Some TLR’s need to be on the outside and some on the inside.

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• TLR trigger a common pathway of intracellular signaling1. Adaptor protein MyD882. Interleukin-1 receptor associated kinase (IRAK)3. Translocation of TF nuclear factor B (NFB) from cytoplasm to the nucleus4. Directs the transcription of genes for inflammatory cytokines

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TLR-4 Can also Signal Interferon alpha and Beta Synthesis and

Secretion

• The two interferons are needed during viral infections.

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Activation of resident macrophages induces inflammation at sites of infection

• Development of inflammation in tissue leads to– Local accumulation of fluid accompanied by

• swelling, redness, heat and pain• Changes induced in blood capillaries

increase diameter (dilation) reduction in the rate of blood flow increased permeability to blood vessel wall increased supply of blood = redness and heat

increased permeability of blood vessels allows movement of fluid, plasma proteins and WBC (neutrophils primarily) from the blood capillaries into the tissue = swelling and pain

– Translocation of NFB to macrophage nucleus initiates transcription of proinflammatory cytokines IL-1, IL-6, CXCL8, IL-12 and TNF-

• Look at fig. 2.27 with these cytokines and their functions.

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Chemokines CXCL8 = IL-8 And IL-12

• IL-8 attracts leukocytes (neutrophils) to site of tissue damage or infection

• Direct traffic of leukocytes during their development– Small, (60-140 aa)

• Two major families– Cysteine residues– CC or CXC

• Cells are attracted from blood to infection site by following a concentration gradient of chemokine produced by cells at infection site

• Chemokines interact with target cells by binding specific cell surface receptors signal through associated GTP-binding proteins

• IL-12 activates NK cells– Lymphocyte of the innate immune system– Protect against viral infections

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TNF- released by macrophages induces

protection at the local level

• Causes and consequences of the release of TNF- within a local area– Endothelium (venules)

1. Increased blood flow2. Increased permeability3. Endothelial

adhesiveness for wbc and platelets

– Causes blood in venules to clot

– Prevents spread of infection to the blood (sepsis or septicemia) Fig 2.29

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TNF- can lead to catastrophe when released systemically

• When infection develops in the blood the systemic release of TNF- on endothelium (venules) in all tissues simultaneously induces a state of shock– Organ failure– Death

Fig 2.29

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Fixed Defenses

• Fixed defenses (skin + innate immunity)– Always available– Do not improve with repeated exposure

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Innate Immunity

• Innate immunity works immediately on pathogen confrontation– Chemical weapons include reactive ions, peptides

• kill pathogens directly– Protease inhibitors, clotting cascade and kinin reactions

• Inhibit pathogen colonizing tissues• Spread infections

– Complement • Tags microbial surface proteins

– Specific receptors• Bind chemical parts of microbial macromolecules that are not a

part of self• All of these components work to• Assist phagocytes in destruction of invading pathogens

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Distinct but complementary properties of Macrophages and Neutrophils

Macrophages• Long-lived• Reside in tissues• Work as infection

begins– Raise alarm

Neutrophils• Short-lived dedicated

killers• Circulate in blood• Wait for macrophage

alarm– To enter tissue

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Neutrophils are dedicated phagocytes that are summoned to sites of infection

• Granulocytes– Numerous granules– Polymorphonuclear leukocytes

• Variable and irregular shapes of their nuclei• Microphages• Smaller sized than macrophages• Most abundant wbc (50 billion in circulation)• Life span < 2 days• 60% of hematopoietic activity of bone marrow• Large reserve kept in bone marrow

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Neutrophils are excluded from healthy tissue

• Neutrophils are excluded from healthy tissue– Release of inflammatory mediators at infection sites is

what attracts neutrophils– Become dominant phagocytic cells

• 3 X 109 neutrophils mouth and throat• Arrival of neutrophils is the 1st of a series of rxns

– Inflammatory response

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Inflammatory Response

• Involves recruitment of cells and molecules of innate immunity into sites of infection– Neutrophils pus– Extracellular bacteria

• Ex: S. aureus superficial infections and abscesses that neutrophils tackle in large numbers

– Ex: Pus-forming = pyogenic bacteria

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Leukocyte adhesion molecules

• The four structural classes of adhesion molecule present on white blood cells and the cells with which they interact are: 1. Selectins – are carbohydrate-binding lectins2. Vascular addressins - contain carbohydrate groups to

which selectins bind3. Integrins4. Proteins in the immunoglobulin superfamily

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Leukocyte adhesion molecules

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The homing of neutrophils to infected tissues is induced by

inflammatory mediators

• Neutrophil receptors– Inflammatory mediators

• C5a cleaved during complement activation• CXCL8

– secreted by activated macrophages• Peptides containing N-formylmethionine (not human)

• Ligand binding to neutrophil surface receptor changes in neutrophil adhesion molecules– Assist neutrophils in migrating out of blood capillaries

• Extravasation

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The homing of neutrophils to infected tissues is induced by

inflammatory mediators

• Inflammatory mediators (Cytokines) secreted by macrophages change the ligand expression for the neutrophil receptors on the surface of endothelial cells near the site of infection.

• This allows the neutrophils to exit the blood near the site of infection = Extravasation– 4 steps

• Note that the WBC’s at some point will do something analogous to this process, we are just using neutrophil homing as our model.

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Step 1 cytokines/inflammatory mediators induce selectin expression on vascular

endothelium to bind neutrophilsTransient interaction between neutrophil

(sialyl-Lewis X) and selectin on the endothelium

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Step 2 Rolling adhesion tight binding migration to infection site

Interactions between LFA-1 to ICAM-1Strong interaction is induced by CXCL8 held on ECM proteoglycans chemokine attraction neutrophil squeezes between endothelial cells

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Terms to know

• Weibel-Plade bodies• Inflammatory mediators

– leukotriene LTB4, C5a, histamine– P-selectin– E-selectin

• Diapedesis

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Neutrophils are potent pathogen killers but are themselves programmed to die

• Phagocytosis by neutrophils1. Fc receptors2. Complement receptors – Phagocytosis of complement

opsonized pathogens– On availability of specific Abs

• Opsonized with antibody and complement

• Neutrophil process of phagocytosis is similar to that of macrophages, but– > range of particulate engulfed– > microbicidals – 2 types of granules– devoted to storage & delivery of

antimicrobial weaponry

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Two types of Granules for Killing

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Bacterial agents produced or released by phagocytic cells on the ingestion of

microorganisms (macrophage & neutrophil)

Are toxins or bind to essential nutrients

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Respiratory Burst

• Pathogen engulfed by neutrophil degradative enzymes/toxins fusion of phagosomes with neutrophil granules – Granules = modified lysosomes of hydrolytic degradative enzymes,

NADPH-dependent oxidases & -defensins• NADPH oxidase produces Superoxide radicals which are

converted to Hydrogen peroxide by superoxide dismutase. – Reaction causes an increased consumption of hydrogen ions

raised pH activation of primary and secondary granule contents.• Respiratory burst = Transient increase in oxygen

consumption = purpose is to raise the pH of the phagosome so the granule contents can become active to kill pathogen

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Respiratory Burst Kill pathogens

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Toxic Oxygen species produced during the respiratory burst

can diffuse out and damage host cells

• To limit damage by respiratory burst– Phagocytes synthesize enzymes to inactivate toxic

oxygen species– Ex: catalase

• Catalase degrades H2O2 H2O + O2• What happens to these neutrophils?

– Neutrophils can’t replenish granule contents so the die.

Neutrophils apoptosis phagocytosed by macrophage

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Macrophages produce cytokines:TNF-, IL-1 and IL-6

• A spectrum of biological activity to coordinate the body’s response to infection– To alter energy mobilization to generate “heat cytokines”

act on • hypothalamic temperature-control sites, • muscle • fat cells

• Result in body temperature fever

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What’s the role of fever?

• Helps immune system fight infection– Most bacterial and viral pathogens grow better at T’s

lower than body temperature– Elevated T’s bacteria, viral replication decreases– Ag processing increases– Human cells become more resistant to TNF- deleterious

effects• Systemic effect of TNF-, IL-1 and IL-6 changes

soluble plasma proteins secreted by the hepatocytes acute phase response acute phase proteins

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Inflammatory cytokines raise body temperature and activate hepatocytes to

make the acute-phase response

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Acute phase proteins

• Two of the acute-phase response proteins– C-reactive protein– Mannose-binding lectin

• Enhance complement fixation to pathogen surfaces

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C-reactive protein

• Pentamer of identical subunits (pentraxin family)– Binds to phosphorylcholine component of LPS of

bacterial and fungal cell walls• But not to phosphorylcholine in human cells• Acts as an opsonin• Can bind C1q to initiate classical pathway of

complement fixation in absence of Abs• C-reactive protein binds with C1q stalks• Abs binds with C1q globular heads• but then…• The same sequence of complement reactions

occurs with either C-reactive protein or Ab interacts with pathogen

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Mannose-binding lectin (MBL)

• Binds mannose-containing carbohydrates of bacteria and yeast– Calcium-dependent lectin– MBL molecule similar to C1q– 15 to 18 potential binding sites to attach to the pathogen

surface• Even weak individual interactions with a carbohydrate

structure can be developed into a high-avidity using multipoint attachments

• Mannose containing carbohydrates on human cells do not bind MBL because their geometry does not permit multipoint attachment to MBL

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Acute-phase response increases

the supply of the recognition

molecules of innate immunity

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MBL activates a proteolytic enzyme complex: MBL-associated serine

protease = MASP

• MASP-2 cleaves C4 and C2• Initiates complement activation

– Lectin pathway of complement activation– MBL serves as an opsonin to facilitate bacteria uptake by

monocytes in the blood– Monocytes do not express the macrophage mannose

receptor but have receptors that can bind to MBL molecules coating a bacterial surface

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C-reactive protein and MBL are present at low levels in plasma

• Levels increase during acute-phase response– C-reactive and MBL both bind structures that are

common to pathogens but absent on human cells– Initiate complement activation– Fixation by a pathway almost identical to classical

pathway used by Abs• Abs of the adaptive immune response = similar role to

that of C-reactive protein and MBL in innate immunity• Expand the range of pathogen-recognition molecules• Complement components used in the classical and

lectin pathway are structurally and functionally related to components of the alternative pathway

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• C4 and C3 are similar in function, structure and the thioester bond and C2 and factor B are similar.

• C3 convertases:– Alternative – C3bBb– Classical – C4b2a

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Initiation of the Classical Pathway

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Close structural relationships between components of the alternative,

lectin-mediated & classical pathways of complement activation

Major divergence

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Intracellular Infection:Type I interferons inhibit viral replication

and activate host defenses

• Human cell infected with virus response is secretion of type I interferons (interferon)– Family of interferons different from IFN- secreted

from NK cells, CD8 T cells and CD4 TH1 cells (type II interferon)

– Type I interferon• Interfere with viral replication by infected cells• Alert immune system cells that infection is present• Make virus-infected cells more vulnerable to killer

lymphocyte attack– Almost all cells are susceptible to viral infections– Therefore most cells can make type I interferon as well

as its cell-surface receptor

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Type I interferons inhibit viral replication and activate host defenses

• The type I interferon receptor is always present on cell surfaces– Ready to bind interferon made in response to infection

• Type I interferon is barely detectable in healthy individuals blood– But at infection type I interferon becomes abundant

• Many isotypes of type I interferons– Interferon- (IFN-) = single form in humans– Interferon- (IFN-) = multiple forms– Interferon-, - -, - and -

• Similar structure• Bind to same cell-surface receptor• Specified by linked genes on human Chr 9

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Virus-infected cells are stimulated to produce type 1 interferons

• Trigger signals that lead to phosphorylation, dimerization and passage of TF interferon response factor 2 (IRF3) into nucleus

• TF NFB and AP-1 mobilize and coordinate with IRF3 to turn on transcription of the IFN- gene

• Secreted IFN- binds to the IFN receptor on the infected cell surface

• Autocrine mobilization of other IFN-response factors to change gene expression patterns to produce the interferon response

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Virus-infected cells are stimulated to produce type 1 interferons

• IRF7 turning on transcription of the IFN- gene

• Without the need for AP-1 or NFB

• Secreted IFN- will also bind to the interferon receptor expressed by nearby cells that are not infected by the virus

• Acting in paracrine fashion to induce the interferon response that helps these cells to resist infection

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In addition to interfering with viral replication…

• IFN induces cellular changes that make the infected cell more likely to be attacked by killer lymphocytes

• NK cells of innate immunity secrete cytokines and kill infected cells– IFN- or IFN- binds to circulating NK’s cell IFN receptor– NK cells become activated and migrate to infected

tissues– NK cells attack virus-infected cells

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Major functions of type I interferons

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Almost all human cells can secrete type I interferon

• Specialized type I interferon secretors– Interferon-producing cells or Natural interferon-producing

cells• 1000-fold more interferon • Present in blood• <1% of total leukocytes• Cytoplasm resembles a plasma cell

– (i.e. also involved in massive productions of secreted proteins)

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NK cells provide an early defense against intracellular infections

• Natural killer cells (NK cell)– 2nd type of cytotoxic lymphocyte (CTLs)– 3rd type of lymphocyte that is distinct from B- and T-cells– No rearrangement of B or T cell receptor genes– Large lymphocytes– Circulate in the blood– Well developed cytoplasm with cytotoxic granules– Provide innate immunity against intracellular infections– Migrate from blood to infection site in response to

inflammatory cytokines• Two effector functions

– Cell killing– Secretion of cytokines

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NK cells provide an early response to virus infection

• NK cells can kill certain types of target cells– Base level of cytotoxicity is 20-100 fold > on exposure to

IFN- and IFN- produced in response to viral infection• Type I interferon induce proliferation of NK

– In addition to activation by type I interferons, NK cells are also activated by IL-12 (macrophages) and TNF- (macrophages)

• Four key cytokines produce activated NK cells early in an infection– Stimulation of NK cells with IFN- and IFN- favors the

development of cytotoxic effector function– Stimulation of NK cells IL-12 release favors the

production of cytokines

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NK cells provide an early response to virus infection

effector T cells take over to finish the job

• IFN- favorite cytokine “released” by NK cells activates macrophage positive feedback loop macrophage secretes IL-12 and NK secretes its principal cytokine IFN-

• Effector T cells enter the site of infection become major source of IFN- and cell-mediated cytotoxicity secrete inhibitory cytokine IL-10 turn off NK cells

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NK cells provide an early response to virus infection

• Infection cytokine burst• NK cell proliferation and

activation– Wave emerging after cytokine

release• NK cell control of virus

replication and spread of infection

• CD8 T cells develop

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NK-cell receptors differ in the ligands they bind and the signals they generate

• Partially activated NK cells circulate in blood – Waiting on macrophages to sound the alarm– What keeps these NK cells in state of readiness

• NK-cell receptors– Some can provide activating and some can

provide inhibitory signals• Two major classes of NK-cell receptors

– NK-cell Immunoglobulin-like receptors– NK-cell Lectin-like receptors

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NK cells express diverse inhibitory and activating receptors

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NK-cell Killing: A Balancing Act

• The one requirement of NK-cell receptors– They must inhibit the NK cell from killing healthy self-cells

• Balancing act between activating and inhibitory signals – When a cell is infected, malignant or has received trauma

the protein expression will be changed and the amount of activating signals > inhibitory signals NK-cell killing

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Three genetic complexes contribute to NK-cell recognition of ‘missing-self”

• Intracellular parasite changes the expression or conformation of MHC class I

• Interaction of the cell with receptors on NK cell generates a stimulatory signal

• NK cell allowed to kill the infected cell