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Chapter 21 16 The Immune System: Innate & Adaptive Body Defenses Immunity • Resistance to disease • Immune system has two intrinsic systems – Innate (nonspecific) defense system – Adaptive (specific) defense system Immunity 1. Innate defense system has two lines of defense – First line of defense is external body membranes (skin and mucosae) – Second line of defense is antimicrobial proteins, phagocytes, and other cells • Inhibit spread of invaders • Inflammation is its most important mechanism Immunity 2. Adaptive defense system –Third line of defense attacks particular foreign substances • Takes longer to react than the innate system • Innate and adaptive defenses are deeply intertwined Surface barriers • Skin • Mucous membranes Innate defenses Internal defenses • Phagocytes • NK cells • Inflammation • Antimicrobial proteins • Fever Humoral immunity • B cells Adaptive defenses Cellular immunity • T cells Figure 21.1 Innate Defenses • Surface barriers – Skin, mucous membranes, and their secretions • Physical barrier to most microorganisms • Keratin is resistant to weak acids and bases, bacterial enzymes, and toxins – Mucosae provide similar mechanical barriers Surface Barriers • Protective chemicals inhibit or destroy microorganisms – Skin acidity – Lipids in sebum and dermcidin in sweat – HCl and protein-digesting enzymes of stomach mucosae – Lysozyme of saliva and lacrimal fluid – Mucus with defensins Surface Barriers • Respiratory system modifications – Mucus-coated hairs in the nose – Cilia of upper respiratory tract sweep dust- and bacteria-laden mucus from lower respiratory passages Internal Defenses: Cells and Chemicals • Necessary if microorganisms invade deeper tissues – Phagocytes – Natural killer (NK) cells – Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals) – Antimicrobial proteins (interferons and complement proteins) – Fever Phagocytes: Macrophages • Macrophages develop from monocytes to become the chief phagocytic cells • Free macrophages wander through tissue spaces – E.g., alveolar macrophages • Fixed macrophages are permanent residents of some organs – E.g., Kupffer cells (liver) and microglia (brain) Phagocytes: Neutrophils • Neutrophils – Become phagocytic on encountering infectious material in tissues Mechanism of Phagocytosis Step 1: Adherence of phagocyte to pathogen – Facilitated by opsonization—coating of pathogen by complement proteins or antibodies Innate defenses Internal defenses (a) A macrophage (purple) uses its cytoplasmic extensions to pull spherical bacteria (green) toward it. Scanning electron micrograph (1750x). Figure 21.2a 1 Phagocyte adheres to pathogens or debris. Lysosome Phagosome (phagocytic vesicle) Acid hydrolase enzymes (b) Events of phagocytosis. 2 Phagocyte forms pseudopods that eventually engulf the particles forming a phagosome. 3 Lysosome fuses with the phagocytic vesicle, forming a phagolysosome. 4 Lysosomal enzymes digest the particles, leaving a residual body. 5 Exocytosis of the vesicle removes indigestible and residual material. Figure 21.2b Mechanism of Phagocytosis • Destruction of pathogens – Acidification and digestion by lysosomal enzymes – Respiratory burst • Release of cell-killing free radicals • Activation of additional enzymes – Oxidizing chemicals (e.g. H2O2) – Defensins (in neutrophils) Natural Killer (NK) Cells • Large granular lymphocytes • Target cells that lack “self” cell-surface receptors • Induce apoptosis in cancer cells and virusinfected cells • Secrete potent chemicals that enhance the inflammatory response Inflammatory Response • Triggered whenever body tissues are injured or infected • Prevents the spread of damaging agents • Disposes of cell debris and pathogens • Sets the stage for repair Inflammatory Response • Cardinal signs of acute inflammation: 1. Redness 2. Heat 3. Swelling 4. Pain (And sometimes 5. Impairment of function) Inflammatory Response • Macrophages and epithelial cells of boundary tissues bear Toll-like receptors (TLRs) • TLRs recognize specific classes of infecting microbes • Activated TLRs trigger the release of cytokines that promote inflammation Inflammatory Response • Inflammatory mediators – Histamine (from mast cells) – Blood proteins – Kinins, prostaglandins (PGs), leukotrienes, and complement • Released by injured tissue, phagocytes, lymphocytes, basophils, and mast cells Vasodilation and Increased Vascular Permeability • Inflammatory chemicals cause – Dilation of arterioles, resulting in hyperemia – Increased permeability of local capillaries and edema (leakage of exudate) • Exudate contains proteins, clotting factors, and antibodies Inflammatory Response: Edema • Functions of the surge of exudate – Moves foreign material into lymphatic vessels – Delivers clotting proteins to form a scaffold for repair and to isolate the area Innate defenses Tissue injury Internal defenses Release of chemical mediators (histamine, complement, kinins, prostaglandins, etc.) Release of leukocytosisinducing factor Leukocytosis (increased numbers of white blood cells in bloodstream) Initial stimulus Vasodilation of arterioles Increased capillary permeability Local hyperemia (increased blood flow to area) Capillaries leak fluid (exudate formation) Attract neutrophils, monocytes, and lymphocytes to area (chemotaxis) Leukocytes migrate to injured area Margination (leukocytes cling to capillary walls) Physiological response Signs of inflammation Leaked protein-rich fluid in tissue spaces Result Heat Redness Locally increased temperature increases metabolic rate of cells Pain Swelling Possible temporary limitation of joint movement Leaked clotting proteins form interstitial clots that wall off area to prevent injury to surrounding tissue Temporary fibrin patch forms scaffolding for repair Diapedesis (leukocytes pass through capillary walls) Phagocytosis of pathogens and dead tissue cells (by neutrophils, short-term; by macrophages, long-term) Pus may form Area cleared of debris Healing Figure 21.3 Phagocyte Mobilization • Neutrophils, then phagocytes flood to inflamed sites Phagocyte Mobilization • Steps for phagocyte mobilization 1. Leukocytosis: release of neutrophils from bone marrow in response to leukocytosis-inducing factors from injured cells 2. Margination: neutrophils cling to the walls of capillaries in the inflamed area 3. Diapedesis of neutrophils 4. Chemotaxis: inflammatory chemicals (chemotactic agents) promote positive chemotaxis of neutrophils Innate defenses Internal defenses Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents. Leukocytosis. Neutrophils enter blood from bone marrow. 1 Margination. Neutrophils cling to capillary wall. 2 Chemotaxis. Neutrophils follow chemical trail. 4 Capillary wall Basement membrane Endothelium Diapedesis. Neutrophils flatten and squeeze out of capillaries. 3 Figure 21.4 Antimicrobial Proteins • Interferons (IFNs) and complement proteins – Attack microorganisms directly – Hinder microorganisms’ ability to reproduce Interferons • Viral-infected cells are activated to secrete IFNs • IFNs enter neighboring cells • Neighboring cells produce antiviral proteins that block viral reproduction Innate defenses Virus Viral nucleic acid 1 Virus enters cell. Internal defenses New viruses 5 Antiviral proteins block viral reproduction. 2 Interferon genes switch on. DNA Nucleus mRNA 4 Interferon 3 Cell produces interferon molecules. Interferon Host cell 2 Host cell 1 Binds interferon Infected by virus; from cell 1; interferon makes interferon; induces synthesis of is killed by virus protective proteins binding stimulates cell to turn on genes for antiviral proteins. Figure 21.5 Interferons • Produced by a variety of body cells – Lymphocytes produce gamma (), or immune, interferon – Most other WBCs produce alpha () interferon – Fibroblasts produce beta () interferon – Interferons also activate macrophages and mobilize NKs Interferons • Functions – Anti-viral – Reduce inflammation – Activate macrophages and mobilize NK cells • Genetically engineered IFNs for – Antiviral agents against hepatitis and genital warts virus – Multiple sclerosis treatment Complement • ~20 blood proteins that circulate in an inactive form • Include C1–C9, factors B, D, and P, and regulatory proteins • Major mechanism for destroying foreign substances Complement • Amplifies all aspects of the inflammatory response • Kills bacteria and certain other cell types by cell lysis • Enhances both nonspecific and specific defenses Complement Activation • Two pathways 1. Classic pathway • Antibodies bind to invading organisms • C1 binds to the antigen-antibody complexes (complement fixation) 2. Alternative pathway • Triggered when activated C3, B, D, and P interact on the surface of microorganisms Complement Activation • Each pathway involves activation of proteins in an orderly sequence • Each step catalyzes the next • Both pathways converge on C3, which cleaves into C3a and C3b Complement Activation • Activated complement – Enhances inflammation – Promotes phagocytosis – Causes cell lysis • C3b initiates formation of a membrane attack complex (MAC) • MAC causes cell lysis by inducing a massive influx of water • C3b also causes opsonization, and C3a causes inflammation Classic pathway Antigen-antibody complex + complex Opsonization: coats pathogen surfaces, which enhances phagocytosis Insertion of MAC and cell lysis (holes in target cell’s membrane) Alternative pathway Spontaneous activation + Stabilizing factors (B, D, and P) + No inhibitors on pathogen surface Enhances inflammation: stimulates histamine release, increases blood vessel permeability, attracts phagocytes by chemotaxis, etc. Pore Complement proteins (C5b–C9) Membrane of target cell Figure 21.6 Fever • Systemic response to invading microorganisms • Leukocytes and macrophages exposed to foreign substances secrete pyrogens • Pyrogens reset the body’s thermostat upward • High fevers are dangerous = heat denatures enzymes • Benefits of moderate fever – Causes the liver and spleen to sequester iron and zinc (needed by microorganisms) – Increases metabolic rate, which speeds up repair Adaptive Defenses • The adaptive immune (specific defense) system – Protects against infectious agents and abnormal body cells – Amplifies the inflammatory response – Activates complement Adaptive Defenses • Adaptive immune response – Is specific – Is systemic – Has memory • Two separate overlapping arms 1. Humoral (antibody-mediated) immunity 2. Cellular (cell-mediated) immunity Antigens • Substances that can mobilize the adaptive defenses and provoke an immune response • Most are large, complex molecules not normally found in the body (nonself) Complete Antigens • Important functional properties – Immunogenicity: ability to stimulate proliferation of specific lymphocytes and antibodies – Reactivity: ability to react with products of activated lymphocytes and antibodies released • Examples: foreign protein, polysaccharides, lipids, and nucleic acids Haptens (Incomplete Antigens) • Small molecules (peptides, nucleotides, and hormones) • Not immunogenic by themselves • Are immunogenic when attached to body proteins • Cause the immune system to mount a harmful attack • Examples: poison ivy, animal dander, detergents, and cosmetics Antigenic Determinants • Certain parts of an entire antigen that are immunogenic • Antibodies and lymphocyte receptors bind to them • Most naturally occurring antigens have numerous antigenic determinants that – Mobilize several different lymphocyte populations – Form different kinds of antibodies against it • Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity Antibody A Antigenbinding sites Antigenic determinants Antigen Antibody B Antibody C Figure 21.7 Self-Antigens: MHC Proteins • Protein molecules (self-antigens) on the surface of cells • Antigenic to others in transfusions or grafts • Example: MHC proteins – Coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual MHC Proteins • Classes of MHC proteins – Class I MHC proteins, found on virtually all body cells – Class II MHC proteins, found on certain cells in the immune response • MHC proteins display peptides (usually self-antigens) • In infected cells, MHC proteins display fragments of foreign antigens, which help mobilize Cells of the Adaptive Immune System • Two types of lymphocytes – B lymphocytes (B cells)—humoral immunity – T lymphocytes (T cells)—cell-mediated immunity • Antigen-presenting cells (APCs) – Do not respond to specific antigens – Play essential auxiliary roles in immunity Lymphocytes • Originate in red bone marrow – B cells mature in the red bone marrow – T cells mature in the thymus Lymphocytes • When mature, they have – Immunocompetence; they are able to recognize and bind to a specific antigen – Self-tolerance – unresponsive to self antigens • Naive (unexposed) B and T cells are exported to lymph nodes, spleen, and other lymphoid organs Adaptive defenses Immature lymphocytes Red bone marrow: site of lymphocyte origin Humoral immunity Cellular immunity Primary lymphoid organs: site of development of immunocompetence as B or T cells Secondary lymphoid organs: site of antigen encounter, and activation to become effector and memory B or T cells Red bone marrow 1 Lymphocytes destined to become T cells migrate (in blood) to the thymus and develop immunocompetence there. B cells develop immunocompetence in red bone marrow. Thymus Bone marrow 2 Immunocompetent but still naive Lymph nodes, spleen, and other lymphoid tissues lymphocytes leave the thymus and bone marrow. They “seed” the lymph nodes, spleen, and other lymphoid tissues where they encounter their antigen. 3 Antigen-activated immunocompetent lymphocytes (effector cells and memory cells) circulate continuously in the bloodstream and lymph and throughout the lymphoid organs of the body. Figure 21.8 T Cells • T cells mature in the thymus under negative and positive selection pressures – Positive selection • Selects T cells capable of binding to self-MHC proteins (MHC restriction) – Negative selection • Prompts apoptosis of T cells that bind to self-antigens displayed by self-MHC • Ensures self-tolerance Adaptive defenses Cellular immunity Positive selection: T cells must recognize self major histocompatibility proteins (self-MHC). AntigenDeveloping presenting T cell thymic cell Failure to recognize self-MHC results in apoptosis (death by cell suicide). MHC T cell receptor Self-antigen Recognizing self-MHC results in MHC restriction—survivors are restricted to recognizing antigen on self-MHC. Survivors proceed to negative selection. Negative selection: T cells must not recognize self-antigens. Recognizing self-antigen results in apoptosis. This eliminates self-reactive T cells that could cause autoimmune diseases. Failure to recognize (bind tightly to) self-antigen results in survival and continued maturation. Figure 21.9 B Cells • B cells mature in red bone marrow • Self-reactive B cells – Are eliminated by apoptosis (clonal deletion) or – Undergo receptor editing – rearrangement of their receptors – Are inactivated (anergy) if they escape from the bone marrow Antigen Receptor Diversity • Lymphocytes make up to a billion different types of antigen receptors – Coded for by ~25,000 genes – Gene segments are shuffled by somatic recombination • Genes determine which foreign substances the immune system will recognize and resist Antigen-Presenting Cells (APCs) • Engulf antigens • Present fragments of antigens to be recognized by T cells • Major types – Dendritic cells in connective tissues and epidermis – Macrophages in connective tissues and lymphoid organs – B cells Figure 21.10 Macrophages and Dendritic Cells • Present antigens and activate T cells – Macrophages mostly remain fixed in the lymphoid organs – Dendritic cells internalize pathogens and enter lymphatics to present the antigens to T cells in lymphoid organs • Activated T cells release chemicals that – Prod macrophages to become insatiable phagocytes and to secrete bactericidal chemicals Adaptive Immunity: Summary • Uses lymphocytes, APCs, and specific molecules to identify and destroy nonself substances • Depends upon the ability of its cells to – Recognize antigens by binding to them – Communicate with one another so that the whole system mounts a specific response Humoral Immunity Response • Antigen challenge – First encounter between an antigen and a naive immunocompetent lymphocyte – Usually occurs in the spleen or a lymph node • If the lymphocyte is a B cell – The antigen provokes a humoral immune response – Antibodies are produced Clonal Selection 1. B cell is activated when antigens bind to its surface receptors and cross-link them 2. Receptor-mediated endocytosis of crosslinked antigen-receptor complexes occurs 3. Stimulated B cell grows to form a clone of identical cells bearing the same antigenspecific receptors (T cells are usually required to help B cells achieve full activation) Fate of the Clones • Most clone cells become plasma cells – secrete specific antibodies at the rate of 2000 molecules per second for four to five days Fate of the Clones • Secreted antibodies – Circulate in blood or lymph – Bind to free antigens – Mark the antigens for destruction Fate of the Clones • Clone cells that do not become plasma cells become memory cells – Provide immunological memory – Mount an immediate response to future exposures of the same antigen Adaptive defenses Humoral immunity Primary response (initial encounter with antigen) Activated B cells Plasma cells (effector B cells) Secreted antibody molecules Antigen Proliferation to form a clone Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with non-complementary receptors remain inactive) Memory B cell— primed to respond to same antigen Figure 21.11 (1 of 2) Immunological Memory • Primary immune response – Occurs on the first exposure to a specific antigen – Lag period: three to six days – Peak levels of plasma antibody are reached in 10 days – Antibody levels then decline Immunological Memory • Secondary immune response – Occurs on re-exposure to the same antigen – Sensitized memory cells respond within hours – Antibody levels peak in two to three days at much higher levels – Antibodies bind with greater affinity – Antibody level can remain high for weeks to months Adaptive defenses Humoral immunity Primary response (initial encounter with antigen) Activated B cells Proliferation to form a clone Plasma cells (effector B cells) Memory B cell— primed to respond to same antigen Secreted antibody molecules Secondary response (can be years later) Antigen Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with non-complementary receptors remain inactive) Clone of cells identical to ancestral cells Subsequent challenge by same antigen results in more rapid response Plasma cells Secreted antibody molecules Memory B cells Figure 21.11 Secondary immune response to antigen A is faster and larger; primary immune response to antigen B is similar to that for antigen A. Primary immune response to antigen A occurs after a delay. Antibodies to B Antibodies to A First exposure to antigen A Second exposure to antigen A; first exposure to antigen B Time (days) Figure 21.12 Active Humoral Immunity • Occurs when B cells encounter antigens and produce specific antibodies against them – Two types • Naturally acquired—response to a bacterial or viral infection • Artificially acquired—response to a vaccine of dead or attenuated pathogens Active Humoral Immunity • Vaccines – Spare us the symptoms of the primary response – Provide antigenic determinants that are immunogenic and reactive – Target only one type of helper T cell, so fail to fully establish cellular immunological memory Passive Humoral Immunity • B cells are not challenged by antigens • Immunological memory does not occur Passive Humoral Immunity • Two types 1. Naturally acquired—antibodies delivered to a fetus via the placenta or to infant through milk 2. Artificially acquired—injection of serum, such as gamma globulin • Protection is immediate but ends when antibodies naturally degrade in the body Humoral immunity Active Passive Naturally acquired Artificially acquired Naturally acquired Artificially acquired Infection; contact with pathogen Vaccine; dead or attenuated pathogens Antibodies pass from mother to fetus via placenta; or to infant in her milk Injection of immune serum (gamma globulin) Figure 21.13 Antibodies • Immunoglobulins—gamma globulin portion of blood • Proteins secreted by plasma cells • Capable of binding specifically with antigen detected by B cells Basic Antibody Structure • T-or Y-shaped monomer of four looping linked polypeptide chains • Two identical heavy (H) chains and two identical light (L) chains • Variable (V) regions of each arm combine to form two identical antigen-binding sites Basic Antibody Structure • Constant (C) region or stem determines: – The antibody class (IgM, IgA, IgD, IgG, or IgE) – The cells & chemicals that the antibody can bind to – How the antibody class functions in antigen elimination Antigen-binding site Heavy chain variable region Heavy chain constant region Light chain variable region Light chain constant region Disulfide bond Hinge region Stem region (a) Figure 21.14a Generating Antibody Diversity • Billions of antibodies result from somatic recombination of gene segments • Hypervariable regions of some genes increase antibody variation through somatic mutations • Each plasma cell can switch the type of H chain produced, making an antibody of a different class Antibody Targets • Antibodies inactivate and tag antigens – Form antigen-antibody (immune) complexes • Defensive mechanisms used by antibodies – Neutralization and agglutination (the two most important) – Precipitation and complement fixation Neutralization • Simplest mechanism • Antibodies block specific sites on viruses or bacterial exotoxins • Prevent these antigens from binding to receptors on tissue cells • Antigen-antibody complexes undergo phagocytosis Agglutination • Antibodies bind the same determinant on more than one cell-bound antigen • Cross-linked antigen-antibody complexes agglutinate – Example: clumping of mismatched blood cells Precipitation • Soluble molecules are cross-linked • Complexes precipitate and are subject to phagocytosis Complement Fixation and Activation • Main antibody defense against cellular antigens • Several antibodies bind close together on a cellular antigen • Their complement-binding sites trigger complement fixation into the cell’s surface • Complement triggers cell lysis Complement Fixation and Activation • Activated complement functions – Amplifies the inflammatory response – Opsonization – Enlists more and more defensive elements Adaptive defenses Humoral immunity Antigen Antigen-antibody complex Antibody Inactivates by Neutralization (masks dangerous parts of bacterial exotoxins; viruses) Agglutination (cell-bound antigens) Enhances Phagocytosis Fixes and activates Precipitation (soluble antigens) Enhances Complement Leads to Inflammation Cell lysis Chemotaxis Histamine release Figure 21.15 Monoclonal Antibodies • Commercially prepared pure antibody • Produced by hybridomas – Cell hybrids: fusion of a tumor cell and a B cell • Proliferate indefinitely and have the ability to produce a single type of antibody • Used in research, clinical testing, and cancer treatment Cell-Mediated Immune Response • T cells provide defense against intracellular antigens – Two types of surface receptors of T cells • T cell antigen receptors • Cell differentiation glycoproteins – CD4 or CD8 – Play a role in T cell interactions with other cells Cell-Mediated Immune Response • Major types of T cells – CD4 cells become helper T cells (TH) when activated – CD8 cells become cytotoxic T cells (TC) that destroy cells harboring foreign antigens • Other types of T cells – Regulatory T cells (TREG) – Memory T cells Adaptive defenses Cellular immunity Immature lymphocyte Red bone marrow T cell receptor Class II MHC protein T cell receptor Maturation CD4 cell Thymus Activation APC (dendritic cell) Activation Memory cells CD4 Class I MHC protein CD8 cell APC (dendritic cell) CD8 Lymphoid tissues and organs Helper T cells (or regulatory T cells) Effector cells Blood plasma Cytotoxic T cells Figure 21.16 Comparison of Humoral and CellMediated Response • Antibodies of the humoral response – The simplest ammunition of the immune response • Targets – Bacteria and molecules in extracellular environments (body secretions, tissue fluid, blood, and lymph) Comparison of Humoral and CellMediated Response • T cells of the cell-mediated response – Recognize and respond only to processed fragments of antigen displayed on the surface of body cells • Targets – Body cells infected by viruses or bacteria – Abnormal or cancerous cells – Cells of infused or transplanted foreign tissue Antigen Recognition • Immunocompetent T cells are activated when their surface receptors bind to a recognized antigen (nonself) • T cells must simultaneously recognize – Nonself (the antigen) – Self (an MHC protein of a body cell) MHC Proteins • Two types of MHC proteins are important to T cell activation – Class I MHC proteins - displayed by all cells except RBCs – Class II MHC proteins – displayed by APCs (dendritic cells, macrophages and B cells) • Both types are synthesized at the ER and bind to peptide fragments Class I MHC Proteins • Bind with fragment of a protein synthesized in the cell (endogenous antigen) • Endogenous antigen is a self-antigen in a normal cell; a nonself antigen in an infected or abnormal cell • Informs cytotoxic T cells of the presence of microorganisms hiding in cells (cytotoxic T cells ignore displayed self-antigens) Cytoplasm of any tissue cell 2 Endogenous antigen 1 Endogenous peptides enter ER via antigen is degraded transport protein. by protease. Endogenous antigen— self-protein or foreign (viral or cancer) protein Cisternae of endoplasmic reticulum (ER) 3 Endogenous antigen peptide is loaded onto class I MHC protein. 4 Loaded MHC protein migrates in vesicle to the plasma membrane, where it displays the antigenic peptide. Transport protein (ATPase) Plasma membrane of a tissue cell Antigenic peptide Extracellular fluid (a) Endogenous antigens are processed and displayed on class I MHC of all cells. Figure 21.17a Class II MHC Proteins • Bind with fragments of exogenous antigens that have been engulfed and broken down in a phagolysosome • Recognized by helper T cells Cytoplasm of APC 1a Class II MHC is synthesized in ER. Invariant chain prevents class II MHC from binding to peptides in the ER. 3 Vesicle fuses with phagolysosome. Invariant chain is removed, and antigen is loaded. 2a Cisternae of endoplasmic Phagosome reticulum (ER) 1b Extracellular antigen (bacterium) is phagocytized. Class II MHC is exported from ER in a vesicle. 4 Vesicle with loaded MHC migrates to the plasma membrane. 2b Phagosome merges with lysosome, forming a phagolysosome; antigen is degraded. Extracellular antigen Extracellular fluid Lysosome Plasma membrane of APC Antigenic peptide (b) Exogenous antigens are processed and displayed on class II MHC of antigen-presenting cells (APCs). Figure 21.17b T Cell Activation • • APCs (most often a dendritic cell) migrate to lymph nodes and other lymphoid tissues to present their antigens to T cells T cell activation is a two-step process 1. Antigen binding 2. Co-stimulation T Cell Activation: Antigen Binding • CD4 and CD8 cells bind to different classes of MHC proteins (MHC restriction) • CD4 cells bind to antigen linked to class II MHC proteins of APCs • CD8 cells are activated by antigen fragments linked to class I MHC of APCs T Cell Activation: Antigen Binding • Dendritic cells are able to obtain other cells’ endogenous antigens by – Engulfing dying virus-infected or tumor cells – Importing antigens through temporary gap junctions with infected cells • Dendritic cells then display the endogenous antigens on both class I and class II MHCs T Cell Activation: Antigen Binding • TCR that recognizes the nonself-self complex is linked to multiple intracellular signaling pathways • Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition) • Antigen binding stimulates the T cell, but costimulation is required before proliferation can occur Adaptive defenses Cellular immunity 1 Dendritic cell Viral antigen Dendritic cell T cell receptor (TCR) Clone formation Class lI MHC protein displaying processed viral antigen CD4 protein engulfs an exogenous antigen, processes it, and displays its fragments on class II MHC protein. 2 Immunocompetent CD4 cell recognizes antigen-MHC complex. Both TCR and CD4 protein bind Immunocom- to antigen-MHC complex. petent CD4 T cell 3 CD4 cells are activated, proliferate (clone), and become memory and effector cells. Helper T memory cell Activated helper T cells Figure 21.18 T Cell Activation: Co-Stimulation • Requires T cell binding to other surface receptors on an APC – Dendritic cells and macrophages produce surface B7 proteins when innate defenses are mobilized – B7 binding with a CD28 receptor on a T cell is a crucial costimulatory signal • Cytokines (interleukin 1 and 2 from APCs or T cells) trigger proliferation and differentiation of activated T cell T Cell Activation: Co-Stimulation • Without co-stimulation, anergy occurs – T cells • Become tolerant to that antigen • Are unable to divide • Do not secrete cytokines T Cell Activation: Co-Stimulation • T cells that are activated – Enlarge, proliferate, and form clones – Differentiate and perform functions according to their T cell class T Cell Activation: Co-Stimulation • Primary T cell response peaks within a week • T cell apoptosis occurs between days 7 and 30 • Effector activity wanes as the amount of antigen declines • Benefit of apoptosis: activated T cells are a hazard • Memory T cells remain and mediate secondary responses Cytokines • Mediate cell development, differentiation, and responses in the immune system • Include interleukins and interferons • Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to – Release interleukin 2 (IL-2) – Synthesize more IL-2 receptors Cytokines • IL-2 is a key growth factor, acting on cells that release it and other T cells – Encourages activated T cells to divide rapidly – Used therapeutically to treat melanoma and kidney cancers • Other cytokines amplify and regulate innate and adaptive responses Roles of Helper T(TH) Cells • Play a central role in the adaptive immune response • Once primed by APC presentation of antigen, they – Help activate T and B cells – Induce T and B cell proliferation – Activate macrophages and recruit other immune cells • Without TH, there is no immune response Helper T Cells • Interact directly with B cells displaying antigen fragments bound to MHC II receptors • Stimulate B cells to divide more rapidly and begin antibody formation • B cells may be activated without TH cells by binding to T cell–independent antigens • Most antigens require TH co-stimulation to activate B cells TH cell help in humoral immunity Activated helper T cell 1 TH cell binds with the Helper T cell CD4 protein self-nonself complexes of a B cell that has encountered its antigen and is displaying it on MHC II on its surface. MHC II protein of B cell displaying processed antigen 2 TH cell releases T cell receptor (TCR) IL- 4 and other cytokines interleukins as co-stimulatory signals to complete B cell activation. B cell (being activated) (a) Figure 21.19a Helper T Cells • Cause dendritic cells to express co-stimulatory molecules required for CD8 cell activation TH cell help in cell-mediated immunity CD4 protein Helper T cell 1 Previously activated TH cell binds dendritic cell. Class II MHC protein APC (dendritic cell) 2 TH cell stimulates IL-2 dendritic cell to express co-stimulatory molecules (not shown) needed to activate CD8 cell. 3 Dendritic cell can Class I MHC protein (b) CD8 protein CD8 T cell now activate CD8 cell with the help of interleukin 2 secreted by TH cell. Figure 21.19b Roles of Cytotoxic T(TC) Cells • Directly attack and kill other cells • Activated TC cells circulate in blood and lymph and lymphoid organs in search of body cells displaying antigen they recognize Roles of Cytotoxic T(TC) Cells • Targets – Virus-infected cells – Cells with intracellular bacteria or parasites – Cancer cells – Foreign cells (transfusions or transplants) Cytotoxic T Cells • Bind to a self-nonself complex • Can destroy all infected or abnormal cells Cytotoxic T Cells • Lethal hit – Tc cell releases perforins and granzymes by exocytosis – Perforins create pores through which granzymes enter the target cell – Granzymes stimulate apoptosis • In some cases, TC cell binds with a Fas receptor on the target cell, and stimulates apoptosis Adaptive defenses Cytotoxic T cell (TC) Cellular immunity 1 TC binds tightly to the target cell when it identifies foreign antigen on MHC I proteins. granzyme molecules from its granules by exocytosis. Granule Perforin TC cell membrane Target cell membrane Target cell 2 TC releases perforin and Perforin pore Granzymes 5 The TC detaches and 3 Perforin molecules insert into the target cell membrane, polymerize, and form transmembrane pores (cylindrical holes) similar to those produced by complement activation. 4 Granzymes enter the target cell via the pores. Once inside, these proteases degrade cellular contents, stimulating apoptosis. searches for another prey. (a) A mechanism of target cell killing by TC cells. Figure 21.20a Natural Killer Cells • Recognize other signs of abnormality – Lack of class I MHC – Antibody coating a target cell – Different surface marker on stressed cells • Use the same key mechanisms as Tc cells for killing their target cells Regulatory T (TReg) Cells • Dampen the immune response by direct contact or by inhibitory cytokines • Important in preventing autoimmune reactions Cell-mediated immunity Antigen (Ag) intruder Humoral immunity Inhibits Inhibits Triggers Adaptive defenses Innate defenses Surface Internal barriers defenses Ag-infected body cell engulfed by dendritic cell Becomes Ag-presenting cell (APC) presents self-Ag complex Activates Free Ags may directly activate B cell Antigenactivated B cells Clone and give rise to Activates Naïve Naïve CD8 CD4 T cells T cells Activated to clone Activated to clone and give rise to Induce and give rise to co-stimulation Memory cytotoxic T cells Activated cytotoxic T cells Memory helper T cells Activated helper T cells Memory B cells Plasma cells (effector B cells) Secrete Cytokines stimulate Together the nonspecific killers and cytotoxic T cells mount a physical attack on the Ag Nonspecific killers (macrophages and NK cells of innate immunity) Antibodies (Igs) Circulating lgs along with complement mount a chemical attack on the Ag Figure 21.21