Transcript T cells

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