Masaya Jimbo

Notes for How The Immune System Works by Lauren Sompayrac

List of Topics Page #

Physical barriers 2

Innate immune system 2

Adaptive immune system 6

Secondary lymphoid organs 19

Turning off the immune system 22

Immunological memory 22

Vaccinations 23

Immunopathology 24

Cancer 30

Three lines of defense against invaders

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 - Physical barriers
- Innate immune system
- Adaptive immune system

Physical barriers
- Skin
o Covers ~2 square meters of surface area
- Mucous membranes
o Lines digestive, respiratory, and reproductive tracts
o Covers ~400 square meters of surface area

Innate immune system

- Very quick response
- Complement system
o Extremely fast
o Composed of ~20 different proteins (produced mainly by the liver) that work together to
punch holes in invaders and to signal to other immune system players
o 3 modes of activation
 Alternative (spontaneous) pathway
• C3 is the most abundant complement protein
• C3 molecules are continuously broken spontaneously into C3a and C3b
• C3b is very reactive and can bind to amino or hydroxyl groups, which
tend to be found on the surfaces of bacteria. If C3b doesn’t bind to one
of these reactive groups in ~60 microseconds, it is neutralized by binding
to water.
• Once C3b is stabilized by reacting with a surface molecule, complement
protein B binds to C3b
• Complement protein D clips off part of B to yield C3bBb (a convertase)
• C3bBb can cut nearby C3 proteins to produce more C3b (and thus
C3bBb), resulting in a positive feedback loop
• C3bBb can cut complement protein C5, and C5b can combine with
complement proteins C6, C7, C8, and C9 to make a membrane attack
complex (MAC)
• MAC can punch a hole in the surface of a bacterium, killing it
 Lectin activation pathway
• The liver produces mannose-binding lectin (MBL). MBL binds to a
carbohydrate molecule (mannose) on the surfaces of many common
pathogens. MBL does not bind to surface carbohydrates of healthy
human cells.
• In the blood, MBL binds to mannose-binding lectin-associated serine
protease (MASP)
• When MBL binds to mannose on a pathogen, MASP functions as a
convertase to generate C3b from C3
• The complement chain reaction proceeds as described for the alternative
pathway
 Classical pathway (fixing complement)
• Depends on IgM antibodies
• In the blood and tissues, ~30 complement proteins get together to form
C1
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 • C1 cannot activate the complement cascade because it is bound to an
inhibitor molecule
• When Fab regions of an IgM bind to an invader, C1 complexes can bind
to its Fc regions. This brings C1 complexes close together.
• If two or more C1 complexes are brought together, their inhibitors fall
off, and C1 can produce C3bBb to initiate the complement cascade
• IgG antibodies can also fix complement, but much less efficiently
because they only have one Fc region per molecule
o How human cells are protected from the complement system
 C3b can be clipped to an inactive form by proteins in the blood. This clipping is
accelerated by an enzyme that is present on the surface of human cells.
 Decay accelerating factor (DAF) on the surface of human cells accelerates the
destruction of C3bBb by other blood proteins
 CD59 (protectin) on the surface of human cells can kick almost-finished MACs
off
o 2 other functions of the complement system
 Facilitation of phagocytosis
• When C3b has attached to the surface of an invader, it can be clipped by
a serum protein to iC3b
• iC3b cannot make MACs, but acts like antibodies by opsonizing
(decorating) the surface of the invader
• Phagocytes have iC3b receptors on their surface
 Recruitment of other immune system players
• C3a and C5a act as chemoattractants that can attract and activate
macrophages and neutrophils where they are needed
• C3a and C5a are called anaphylatoxins, because they can contribute to
anaphylactic shock
- Professional phagocytes
o Phagocytosis
 Macrophage first engulfs bacterium in a phagosome
 The phagosome is taken inside the macrophage and fuses with a lysosome
 Lysosomes contain powerful chemicals and enzymes which can destroy bacteria
o Macrophages
 Sentinels that are present under the skin, in the lungs, and in the tissues
surrounding the intestines
 Origin
• Made from stem cells in the bone marrow
• Exist in the bloodstream as monocytes (~2 billion circulating)
o Monocytes remain in the blood for ~3 days, traveling to
capillaries and looking for openings that allow entry into tissues
o Once in the tissue, monocytes mature into macrophages with a
lifetime of months
 When they phagocytose bacteria, macrophages give off chemicals
• Some chemicals increase blood flow to the vicinity, causing redness
• Some chemicals cause endothelial cells to contract, leaving spaces in
capillaries through which fluid can leak out into tissues. This causes
swelling.

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 • Some chemicals can stimulate nearby nerves, sending pain signals to the
brain
 3 stages of readiness
• Resting state
o Slowly proliferating
o Function primarily as garbage collectors
o Express very few class II MHC molecules on their surface
• Primed (activated) state
o Take larger gulps
o Express more class II MHC molecules, thus functioning as APCs
for helper T cells
o Priming is caused by interferon gamma (IFN-γ), a cytokine
produced by helper T cells and NK cells
• Hyperactivated state
o Attained if the macrophage receives direct signal from an
invader
 Example: lipopolysaccharide (LPS), a component of the
outer cell wall of Gram-negative bacteria, can be shed
and bind to receptors on the surface of primed
macrophages
 Macrophages also have receptors for mannose, the
carbohydrate found on the surface of many common
pathogens
o Stops proliferating and focuses on killing, growing larger and
increasing the rate of phagocytosis
 Number of lysosomes increases, increasing the
efficiency of destruction of ingested invaders
 Production of reactive oxygen molecules increases
 Lysosomal contents can be dumped onto multicellular
parasites that are too large to phagocytose
o Secrete the cytokine tumor necrosis factor (TNF), which can kill
tumor cells and virus-infected cells, and can help activate other
immune system warriors
 During an infection, activated macrophages can facilitate the complement system
• Macrophages produce the complement proteins C3, B, and D
• Macrophages can secrete chemicals that increase the permeability of
nearby blood vessels, allowing more complement proteins to be released
into the tissues
o Neutrophils
 ~20 billion circulate in the blood in inactive state (70% of circulating white blood
cells)
 Produced in the bone marrow
 Programmed to commit apoptosis after ~5 days, in order to minimize damage to
normal tissues
 Not APCs
 Tissue delivery and activation
• In response to bacterial invasion, activated macrophages give off the
cytokines interleukin 1 (IL-1) and TNF. The cytokines signal endothelial

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 cells lining nearby blood vessels to express selectin (SEL) on their
surface.
• Interaction between SEL and selectin ligand on the surface of the
neutrophil causes the neutrophil to slow down in the blood vessel, but
not stop
• C5a and LPS signal to the neutrophil that an inflammatory reaction is
taking place, and the neutrophil expresses integrin (INT) on its surface
• INT binds to intercellular adhesion molecule (ICAM) on the surface of
endothelial cells, and causes the neutrophil to stop
• The chemoattractants C5a and f-met peptides (fragments of bacterial
proteins) allow the neutrophil to exit the blood vessel into tissues, and
migrate to the site of inflammation. Cytokines such as TNF activate
neutrophils as they travel through the tissues, so they arrive at the battle
scene ready to kill.
 Once activated, neutrophils become incredibly phagocytic, produce cytokines
that alert other immune system cells, and give off destructive chemicals that are
pre-made and stored until needed
- Natural killer (NK) cells
o Produced and mature in the bone marrow
o Short-lived with half-life of ~1 week
o Mostly found in the blood, the liver, or the spleen
o Like neutrophils, NK cells employ the “roll, stop, exit” strategy to leave the blood and
enter tissues
o 2 functions
 Produce cytokines when they receive battle signals from other immune system
cells
• Interferon gamma (IFN-γ)
o NK cells produce IFN-γ, which can prime macrophages. These
macrophages can then be hyperactivated by LPS
o Hyperactivated macrophages secrete TNF, which bind to their
own receptors and allow the macrophages to secrete IL-12
o TNF and IL-12 influence NK cells to increase IFN-γ production,
which primes more macrophages and thus initiates a positive
feedback loop
• IL-2
o NK cells produce the growth factor IL-2
o During an infection, TNF produced by macrophages causes NK
cells to express IL-2 receptors on their surface
o NK cells can now react to the IL-2 they make and begin to
proliferate
 Destroy bacteria, parasites, virus-infected cells, fungi, and some cancer cells by
forcing them to commit apoptosis
• NK cells use perforin proteins to inject suicide enzymes to target cells
• Fas ligand on NK cell surface can bind to Fas on target cell surface,
signaling the target cell to commit apoptosis
o 2 types of receptors
 Activating receptors
• Recognize unusual carbohydrates or proteins on the surface of target
cells
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 o NK cells can be activated by the bacterial cell wall component
LPS
o NK cells can be activated by interferon alpha and beta, which are
given off by cells when they are attacked by viruses
• When engaged, motivate the NK cell to kill
 Inhibitory receptors
• Recognize class I MHC molecules on cell surfaces
• When engaged, motivate the NK cell not to kill
- Innate immune system is not very effective against viruses once they enter cells
- Innate immune system activates and functions as the “coach” for the adaptive immune system
o Antigen receptors of the adaptive immune system can recognize any protein molecule in
the universe, but cannot distinguish between dangerous and harmless molecules
o Receptors of the innate immune system are tuned to detect the presence of most common
pathogens
o Receptors of the innate immune system can also detect when uncommon pathogens kill
human cells
o The innate immune system integrates information about an invader, and formulates a
game plan for the adaptive immune system
 The game plan specifies which weapons of the adaptive immune system to
mobilize
 The game plan specifies where in the body the weapons of the adaptive immune
system should be deployed

Adaptive immune system

- Adapts to defend against specific invaders
- Activated by the innate immune system
- Antigen presentation
o Cells present antigens on their cell surface using major histocompatibility complex
(MHC) proteins
o Class I MHC molecules
 Found on most cells in the body
 Inform killer T cells about what is going on inside other cells
• When a cell is infected by a virus, viral peptides are presented on class I
MHC molecules on the cell surface, for inspection by killer T cells
 A cell’s endogenous protein fragments are also presented on class I MHC
molecules
 Made of 1 long chain (heavy chain) and 1 short chain (β2-microglobulin)
• Each chromosome 6 has 3 heavy chain genes (HLA-A, HLA-B, HLA-C)
• HLA proteins are polymorphic, while all humans have the same β2-
microglobulin gene
 The ends of the molecule’s groove are closed
• Antigens must be 8 – 11 amino acids long to fit
 Loading class I MHC molecules
• Proteasomes cut up old and defective proteins into peptides
• Some of these peptides are transported into the ER by TAP1 and TAP2.
TAP preferentially transports peptides that are compatible with class I
MHC molecules.

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 • Compatible peptides are loaded onto class I MHC molecules and carried
to the cell surface
o Class II MHC molecules
 Found only on antigen presenting cells (APCs)
 Inform helper T cells about what is going on outside of cells
• Example: During a bacterial infection, a macrophage will eat the
bacteria, and present bacterial proteins on its surface class II MHC
molecules. Helper T cells scan these molecules for news of bacterial
infection.
 Made of 2 long chains (α and β chains)
• Encoded by genes in the HLA-D region of chromosome 6
• Wildly polymorphic
 The ends of the molecule’s groove are open
• Antigens of 13 – 25 amino acids can fit
 Loading class II MHC molecules
• α and β chains are made in the cytoplasm and transported into the ER,
where they bind to the invariant chain
• Part of the invariant chain (called CLIP) sits in the class II MHC’s
groove and prevents it from picking up other endogenous peptides
• Proteins outside the cell are phagocytosed, and the phagosome merges
with an endosome. Inside the endosome, the exogenous proteins are
chopped up into peptides.
• The invariant chain guides the class II MHC through the Golgi stack to
endosomes. Inside the endosome, most of the invariant chain is
destroyed, and HLA-DM releases CLIP from the MHC’s groove.
• The class II MHC is loaded with exogenous peptides, and transported to
the cell surface
o CD1
 Non-classical MHC molecules that allow killer T cells to examine the lipid
composition of cells
 Like class I MHC molecules, consist of a heavy chain paired with a β2-
microglobulin
 Have grooves that are designed to bind lipids, not peptides
o Antigen presenting cells (APCs)
 Function to activate killer T cells & helper T cells
• Display both class I & class II MHC molecules
• Can provide co-stimulation to killer T cells & helper T cells
o B7 on the APC surface binds to CD28 on T cell surface
 Activated dendritic cells (DCs)
• Sentinel cells that sample antigens out in the tissues
• Part of the innate immune system
• Initiate the immune response by activating virgin T cells in lymph nodes
• Resting state
o Express low levels of B7 and MHC molecules (not very good
APCs)
o 3 ways of activation
 Activated by cytokines from other immune system cells
engaged in battle
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  Activated by chemicals given off from dying cells
 Pattern recognition by Toll-like receptors (TLRs)
• TLR2 identifies proteins of Gram-positive
bacteria
• TLR3 recognizes double-stranded RNA
produced during many viral infections
• TLR4 on cell surface senses the presence of LPS
(Gram-negative bacterial cell wall component)
• TLR7 and TLR9 on phago-lysosome
membranes alert the cell to viruses or bacteria
that have been phagocytosed
o TLR7 detects single-stranded RNA of
viruses
o TLR9 detects double-stranded DNA of
bacteria and herpes simplex virus
• TLRs recognize general features of invaders,
and recognize patterns that are not easily
mutated
• Activated state
o After phagocytosis of antigens in the battle scene, the activated
DC migrates through the lymphatic system to the nearest lymph
node
o Before traveling, activated DCs recruit their own replacements
by secreting chemokines, which encourage monocytes to enter
the tissues and become DCs
o During its journey, the activated DC prepares for activation of
virgin T cells
 The activated DC loads its class II MHC molecules with
antigens from the battle scene
 The activated DC increases expression of class I MHC
molecules, in case it was infected by viruses or parasites
 The activated DC increases production of B7 co-
stimulatory proteins
o Once the DC reaches a lymph node, it only lives for ~1 week
 Activated macrophages
• Remain at the battle scene
• Function as refueling stations for experienced T cells
o Once they have been activated by dendritic cells, T cells enter
the tissues to help with the battle
o These T cells must be continually re-stimulated by activated
macrophages
• Part of the innate immune system
 Activated B cells
• Once activated, B cells increase B7 and class II MHC molecules on their
surface. They can act as APCs for helper T cells.
• After binding its cognate antigen, the cell’s BCR is dragged into the cell.
Antigen is processed and loaded onto class II MHC molecules for
presentation at the cell surface.

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 • Since B cells cannot act as APCs until after the adaptive immune system
has fired up, they are most important during later stages of an infection,
or during subsequent infections. Once activated however, activated B
cells have great advantage over dendritic cells and macrophages.
o Activated B cells can use their BCRs to concentrate small
amounts of antigen for presentation to helper T cells
o Antigen presentation by B cells is extremely fast
- B cells & antibodies
o B cell origins
 Produced and mature in the bone marrow (~1 billion produced each day)
 Mature to become antibody-producing plasma cells
 ~3 billion B cells circulate in the bloodstream
o Structure of IgG antibody
 Made up of 2 pairs of heavy chain (Hc) and light chain (Lc) proteins
 Each molecule has 2 identical hands (Fab regions) that can bind to antigens
 Each molecule has a constant region (Fc) that can bind to Fc receptors on the
surface of cells like macrophages. The structure of the Fc region determines the
antibody’s class.
o Antibody function
 Antibodies can opsonize (decorate) invaders, tagging them for phagocytic
destruction
• When a phagocyte’s Fc receptors bind to antibodies that are opsonizing
an invader, its appetite increases
 Neutralizing antibodies can bind to a virus, and keep the virus either from
entering the cell or from replicating once it has entered the cell
 Once a virus gets into a cell, antibodies cannot gain access to it
o Antibody classes
 Immunoglobulin M (IgM)
• The default antibody class (first antibody made)
• Half-life of ~1 day
• Structure
o Looks like 5 IgG antibodies with Fc regions close together
• Functions
o Very good at fixing complement
o Can bind to viruses and prevent them from infecting cells
 Immunoglobulin D (IgD)
• Tiny fraction of circulating antibodies
• Made from the alternative splicing of the same Hc mRNA used to make
IgM
• Significance unknown
 Immunoglobulin G (IgG)
• 75% of the antibodies in the blood
• Longest-lived antibody class (half-life of ~3 weeks)
• Functions
o IgG antibodies come in a number of different subclasses with
slightly different Fc regions
 IgG1 is very good at opsonizing invaders for
phagocytosis
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  IgG3 fixes complement better than any other IgG
subclass
 IgG3 can also aid NK cells in a process called antibody-
dependent cellular cytotoxicity (ADCC)
• IgG3 can bind to its cognate antigen with its Fab
region, and to an NK cell with its Fc region
• This brings the NK cell close to its target cell,
and also stimulates the NK cell to be a more
effective killer
o Can bind to viruses and prevent them from infecting cells
o Can pass from the mother’s blood into fetal blood by way of the
placenta
 Immunoglobulin A (IgA)
• Most abundant antibody class
• Guards the mucosal surfaces of the body (digestive, respiratory, and
reproductive tracts)
• Structure
o Looks like 2 IgG antibodies with their Fc tails held together by a
clip
o The clip functions as a passport that facilitates transport of IgA
across the intestinal wall
o The clip also makes IgA resistant to acids and enzymes in the
digestive tract
• Function
o IgA antibodies can coat invading pathogens and keep them from
attaching to cells lining the mucosal tracts, collecting them into
clumps that are swept out of the body with mucus or feces
 Rejected bacteria make up ~30% of normal fecal matter
o IgA is secreted into the milk of nursing mothers
 IgA antibodies coat the baby’s intestinal mucosa and
provide protection
o IgA antibodies cannot fix complement
 Immunoglobulin E (IgE)
• Function
o Defends against parasites
 IgE can cause mast cells to degranulate, killing parasites
o Causes allergies and anaphylactic shock
• IgE antibodies live for only ~1 day in the blood. However, once bound
to mast cells they have a half-life of several weeks.
o Antibody generation
 Modular design
• In every B cell, the chromosomes encoding the Hc (chromosome 14)
contain multiple copies of 4 types of DNA modules (V,D,J, and C)
• Each copy of given module is slightly different from the other copies
• To assemble a mature Hc, each B cell randomly mixes and matches the
gene segments to generate antibody diversity

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 • The segments on one chromosome 14 need to be silenced, to prevent 2
different Hc proteins from being made. The rearranged gene segments
on both chromosomes are tested.
o If the gene segments are not joined up in frame, the ribosome
will encounter a stop codon and terminate protein assembly
o If one of the chromosomes manages to join the segments in
frame (productive rearrangement), that chromosome is used to
construct the Hc
o If both chromosomes fail to produce a productive rearrangement,
the B cell dies
• Lc is assembled in a similar way. If the B cell fails to productively
rearrange Lc, the B cell dies
• If the completed Hc and Lc do not fit together properly, the B cell dies
 Junctional diversity
• When gene segments are joined together by modular design, additional
DNA bases are added or deleted to create greater diversity
 Antibodies are expressed on the surface of B cells as B cell receptors (BCR)
o Clonal selection (B cell activation)
 Activation of a virgin B cell requires cross-linking of BCRs via binding to its
cognate antigen, as well as a co-stimulatory signal.
• Cross-linking of BCRs
o To generate a signal, many BCRs must be brought together on
the B cell surface (cross-linking)
o The accessory proteins Igα and Igβ are associated with the Hc
protein and protrude into the cytoplasm of the B cell
o When enough BCRs are cross-linked, enough Igα and Igβ are
brought together to send a signal to the cell nucleus
o BCR signaling is greatly facilitated by the complement system
 When complement fragments opsonize an antigen, the
fragments can be recognized by complement receptors
(called co-receptors) on the B cell surface
 This brings BCRs and co-receptors together on the B
cell surface, greatly amplifying cell signaling by BCR.
The number of BCRs that must be clustered to initiate
signaling is decreased >100-fold.
 This process serves to make B cells exquisitely sensitive
to antigens that the innate immune system has identified
as being dangerous
• Co-stimulatory signal
o T cell-dependent activation
 CD40L on the surface of activated helper T cells bind to
CD40 on the B cell surface
 Helper T cells only recognize protein antigens
o T cell-independent activation
 Cytokines supplied by the innate immune system
provide the co-stimulation
 Can react to protein, carbohydrate, and fat antigens
o Polyclonal activation

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  The antigen (called a mitogen) binds to molecules
(mitogen receptors) on B cell surface that are not BCRs
 The clustering of mitogen receptors causes associated
BCRs to be clustered as well
 A single mitogen can activate many different B cells
with different specificities
 Once activated, B cells begin to proliferate. Each cycle of proliferation takes ~12
hours, and the process lasts ~1 week
 By the end, ~20,000 identical B cells will have been produced
o B cell maturation
 Class switching
• B cell can change the class of antibody it produces
• When a virgin B cell is first activated, it produces mainly IgM and some
IgD
• Controlled by local cytokines produced by helper T cells
o In presence of IL-4 and IL-5, B cells preferentially switch their
class from IgM to IgE
o In presence of IFN-γ, B cells preferentially switch their class
from IgM to IgG3
o In presence of TGF-β, B cells preferentially switch their class
from IgM to IgA
o In the case of T cell-independent activation, class switching does
not take place and mostly IgM are produced
 Somatic hypermutation (affinity maturation)
• BCR genes undergo mutation and selection that can increase the affinity
of the BCR toward its cognate antigen
o The regions of B cell chromosomes containing the V, D, and J
segments (i.e. the regions encoding the Fab region) attain
mutation rates as high as 1 per 1000 bases (normal mutation rate
is 1 per 100 million)
o Maturing B cells need to be continually re-stimulated by their
cognate antigen in order to continue proliferating
o Thus, mutations that increase the affinity of the BCR towards its
cognate antigen are favored
• Occurs after the V, D, and J segments have been selected, and usually
after class-switching has taken place
• Controlled by local cytokines produced by helper T cells
 Career decision
• B cell decides to become either a plasma cell or a memory B cell
• Plasma cells
o Usually travel to the spleen or bone marrow
o Plasma cells then begin to rapidly generate antibodies and
release them into the bloodstream (each plasma cell can generate
~2000 antibodies per second)
o After about a week of producing antibodies, most plasma cells
die
• Memory B cells
o Produced with help from helper T cells

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 o Remember the first exposure to a pathogen, and help defend
against subsequent exposures
o Tolerance induction
 Most B cells are tolerized in the bone marrow
 B cells with receptors that recognize self antigen are given another chance to
rearrange their light chain genes (receptor editing)
 B cells with receptors that do not bind to abundant self antigens are released from
bone marrow to circulate with the blood and lymph. ~10% of B cells pass this
tolerance test, and the rest die by apoptosis.
 The trafficking of virgin B cells is restricted to blood, lymph, and secondary
lymphoid organs. This traffic pattern usually protects them from exposure to self
antigens in tissues which might activate them.
• B cells with receptors that recognize antigens which are abundant in the
secondary lymphoid organs usually are efficiently deleted in the bone
marrow
• Self antigens that are rare enough in the bone marrow to allow self-
reactive B cells to escape deletion usually are also too rare to activate
virgin B cells in the secondary lymphoid organs
 Virgin B cells that escape into the tissues are anergized (neutered) or deleted if
they recognize self antigen, but do not receive the required T cell help
 Maintenance of tolerance in germinal centers
• Once activated in secondary lymphoid organs, B cells can modify their
receptors through somatic hypermutation. This can potentially result in
receptors that recognize self antigen.
• B cells in germinal centers require complement-opsonized cognate
antigen for efficient BCR cross-linking, as well as co-stimulation from
Th cells that recognize the cognate antigen
• If somatic hypermutation causes a B cell’s receptors to recognize self
antigen, that B cell can no longer be stimulated by complement-
opsonized antigen or Th cells. Without continuous stimulation, the B
cell dies by apoptosis.
- T cells
o T cell general features
 There are ~1 trillion T cells in a human
 Produced in the bone marrow, but mature in the thymus
• Because the thymus decreases in activity after puberty, the production of
virgin T cells decreases as a person ages
 T cell receptors (TCRs)
• 2 types: αβ and γδ
• Like antibodies and BCRs, TCRs are also made by mix-and-match,
modular design strategy
• Receptor signaling
o CD3 complex, made up of the proteins γ, δ, ε, and ζ, is anchored
in the T cell membrane with long cytoplasmic tails
o When enough αβ receptors are clustered together (cross-linking),
the associated CD3 complexes recruit kinases and dispatch the
activation signal to the nucleus
o TCR signaling is versatile

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  When T cells are educated in the thymus, TCRs trigger
apoptosis if they recognize MHC plus self peptides
 When TCRs recognize their cognate antigen presented
by MHC molecules, but the T cell does not receive co-
stimulation, the T cell is neutered (anergized)
 When TCRs recognize their cognate antigen presented
by MHC molecules, and the T cell receives co-
stimulation, the TCR signals activation
 CD4 & CD8 co-receptors
• CD4 is found on helper T cells. CD8 is found on killer T cells.
• After a TCR has engaged its cognate antigen presented by an MHC
molecule, CD4 and CD8 then clip on and stabilize the TCR-MHC-
peptide interaction, thereby strengthening the signal sent by the TCR
• When T cells begin maturing in the thymus, they express both CD4 and
CD8 and are thus called CD4+CD8+ cells. As the cells mature,
expression of one is down-regulated.
 Co-stimulation
• In addition to having their TCRs ligated by MHC-peptide, virgin T cells
must also receive co-stimulation for activation. Co-stimulation amplifies
TCR signaling ~100-fold.
• B7 molecules on APCs provide co-stimulation by plugging into CD28
receptors on the T cell surface
• Mechanism
o Lipid rafts contain many of the downstream signaling molecules
o Virgin T cells do not have many lipid rafts on their surface
o Co-stimulation recruits lipid rafts to the T cell surface
• Experienced T cells have a reduced requirement for co-stimulation, since
they already have many lipid rafts on their surface, where they can come
together with TCRs
 Like B cells, T cells also obey the principle of clonal selection
• When a T cell’s receptors bind to their cognate antigen, the T cell
proliferates for ~1 week
o After an invader has been repulsed, most of the invader-specific T cells die off.
However, some activated T cells are set aside as memory cells, which can fire up quickly
on subsequent infections by the same invader.
o Traditional T cells
 >95% of T cells in circulation
 Have αβ receptors and either CD4 or CD8 co-receptor
 Recognize a complex composed of a peptide and an MHC molecule on the
surface of a cell
 Educated in the thymus
 Helper T cells (Th cells)
• Quarterback of the immune system
• Direct the local immune system by secreting cytokines
• Detect problems existing outside of cells
o Th cells recognize antigens presented by APCs on class II MHC
molecules
• Express CD4 co-receptors that can clip onto class II MHC molecules
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• Activation by dendritic cells
o Complete activation takes 4 – 10 hours
o When the Th cell’s TCR finds its match, CD4 co-receptors clip
onto the class II MHC molecules of the DC
o Engagement of TCRs up-regulates expression of adhesion
molecules that glue the Th cell and DC together
o The clustering of TCRs and adhesion molecules at the point of
contact is called an immunological synapse
o Engagement of TCRs up-regulates expression of CD40L, which
plug into CD40 on the DC surface. This results in increased
expression of MHC and co-stimulatory molecules by the DC, as
well as secretion of cytokines that prolong the life of the DC.
o After activation is complete, the Th cell and the DC part
o The activated Th cells stimulate their own proliferation (clonal
selection)
 Virgin Th cells make the growth-factor IL-2
 Once activated, Th cells also express IL-2 receptors on
their surface
• Function of activated Th cells
o Travel from lymph node to lymph node, providing help for B
cells or killer T cells
o Enter tissues to provide help for immune cells at the battle site
• Cytokines secreted by Th cells
o When virgin Th cells are activated, they mainly secrete IL-2
o Once Th cells have proliferated, re-stimulation by an APC
allows them to secrete Th1 or Th2 subset of cytokines.
o The initial choice of cytokine profile is determined by the type of
co-stimulation the Th cell receives. However, Th cells can later
be influenced by cytokines at the battle scene, as well as by other
Th cells
 IL-12 (secreted by activated macrophages) influences Th
cells to secrete Th1 cytokines
 IL-4 influences Th cells to secrete Th2 cytokines
o Th1 cytokines
 Help defend against a viral or bacterial attack
 IL-2
• Stimulates killer T cells and NK cells to
proliferate
• Drives Th1 cell proliferation
 IFN-γ
• Primes macrophages
• Influences B cells during class switching to
produce IgG3 antibodies
• Indirectly influences other Th cells to secrete
Th1 cytokines (by priming macrophages which
then secrete IL-12)
• Decreases Th2 cell proliferation
 TNF
15
 • Activates primed macrophages and NK cells
o Th2 cytokines
 Help defend against parasitic or mucosal infection
 IL-4
• Influences B cells during class switching to
produce IgE antibodies
• Directly influences other Th cells to secrete Th2
cytokines
• Drives Th2 cell proliferation
 IL-5
• Influences B cells during class witching to
produce IgA antibodies
 IL-10
• Decreases Th1 cell proliferation
o Some Th cells remain unbiased as Th0 cells
• Delayed type hypersensitivity (DTH)
o Basis of the tuberculin skin test
 Tuberculin protein injected underneath the skin is taken
up by dendritic cells
 The DCs present tuberculin fragments on class II MHC
molecules
 These DCs express enough MHC and B7 to re-stimulate
memory (experienced) Th cells, but not enough to
activate virgin Th cells
 If the patient has or had tuberculosis in the past,
experienced Th1 cells are reactivated and secrete Th1
cytokines that activate/recruit macrophages and
neutrophils at the site of injection. This results in a local
inflammatory reaction with redness and swelling.
 Killer T cells (cytotoxic T lymphocytes – CTLs)
• Destroy virus-infected cells by triggering them to commit apoptosis
o Killer T cells identify virus-infected cells by detecting viral
peptides on their class I MHC molecules
• Express CD8 co-receptors that can clip onto class I MHC molecules
• Virgin killer T cells are activated by activated dendritic cells, just like Th
cells
• Function of activated killer T cells
o Proliferate rapidly before leaving the lymph node and traveling
to the battle site
o Kill infected cells at the battle site by one of 2 ways
 Perforin helps a CTL deliver granzyme B into the
cytoplasm of its target cell. Granzyme B triggers
apoptosis of the target cell.
 Fas ligand on the CTL surface binds to Fas on the target
cell surface. This binding causes apoptosis of the target
cell.

16
 o When virus-infected cells die by apoptosis, the DNA of
unassembled viruses is destroyed, and completed viruses are
enclosed in apoptotic vesicles and phagocytosed by macrophages
• When many killer T cells are needed at the battle scene, Th1 cells supply
IL-2, which is required for killer T cells to proliferate
• Th cell help is important in generating memory killer T cells
 Natural regulatory T cells (nTregs)
• Help keep other T cells under control
• ~5% of CD4+ cells in the circulation
• Have a relatively strong affinity for self antigens presented by class II
MHC molecules on thymic epithelial cells
• Express a gene called Foxp3
• Travel to secondary lymphoid organs and suppress the activation of
potentially self-reactive T cells
o Non-traditional T cells
 γδ T cells
• Have γδ receptors and do not express CD4 or CD8 co-receptor
• Recognize unpresented antigen
• Most abundant in areas that are in contact with the outside world (e.g.
intestine, uterus, tongue)
• Location of education is unknown
 Natural killer T cells
• ~1% of T cells in circulation
• Have αβ receptors
• Mature in the thymus
• Recognize lipids presented by CD1 MHC molecules
o Tolerance induction
 Tolerance induction in the thymus
• T cells which enter the thymus from the bone marrow have no CD4,
CD8, or TCR. They are also resistant to apoptosis, because they express
little/no Fas and express high levels of anti-apoptotic Bcl-2.
• After entry into the thymus, T cells migrate to the cortex and begin to
proliferate
• The T cells become double positive (DP) cells that express CD4, CD8,
and TCR. They express high levels of Fas on their surface and express
little/no Bcl-2, becoming highly susceptible to apoptosis. Cells that fail
positive or negative selection die.
• MHC restriction (positive selection)
o Occurs in the thymic cortex
o Cortical epithelial cells present MHC-peptide complexes to the T
cells
o If the T cell’s receptors do not recognize any MHC-peptide
complexes, the T cell dies by apoptosis. This ensures that all
mature T cells will have TCRs that recognize MHC-antigen
complexes, and not unpresented antigen.
• The T cells stop expressing either CD4 or CD8, becoming single positive
(SP) cells
• Central tolerance induction (negative selection)
17
 o Occurs in the thymic medulla
o Thymic dendritic cells
 Present MHC-peptide complexes to the T cells
• Thymic dendritic cells do not express tissue-
specific antigens. They can only test T cells
with ubiquitous antigens that all cells produce.
 If the T cell’s receptors recognize the MHC-peptide
complexes, it dies by apoptosis. This ensures that
mature T cells do not cause autoimmune disease by
reacting against self antigens.
o Medullary epithelial cells
 Present MHC-peptide complexes to the T cells
• Medullary epithelial cells express both
ubiquitous and tissue-specific antigens
 If the T cell’s receptors recognize the MHC-peptide
complexes, it dies by apoptosis. This ensures that
mature T cells do not cause autoimmune disease by
reacting against self antigens.
• How the same TCR can signal different outcomes
o Positive selection (survival) results from a relatively weak
interaction between TCRs and MHC-self peptide displayed on
cortical thymic epithelial cells
o Negative selection (death) results from a strong interaction
between TCRs and MHC-self peptide expressed on thymic
dendritic cells or medullary thymic epithelial cells
o Activation results from a strong interaction between TCRs and
MHC-peptide displayed by APCs
• Only ~3% of T cells that enter the screening process will exit from the
thymus
• T cells that recognize self antigens that are rare in the thymus (but more
abundant in tissues) may escape negative selection
 The trafficking of virgin T cells is restricted to blood, lymph, and secondary
lymphoid organs. This traffic pattern usually protects them from exposure to self
antigens in tissues which might activate them.
• T cells with receptors that recognize antigens which are abundant in the
secondary lymphoid organs usually are efficiently deleted in the thymus
• Self antigens that are rare enough in the thymus to allow self-reactive T
cells to escape deletion usually are also too rare to activate virgin T cells
in the secondary lymphoid organs
 Tolerance induction in secondary lymphoid organs
• Occasionally, self antigens, which are too rare in the thymus to cause
deletion of potentially autoreactive T cells, are released into circulation
(e.g. as a result of injury)
• Natural regulatory T cells (nTregs) suppress the activation of potentially
self-reactive T cells
o Only those T cells that recognize the same self antigen that the
nTreg recognizes will be affected
o Direct contact between an nTreg and an APC is required for the
nTreg to block activation
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 • Semi-mature dendritic cells can tolerize potentially self-reactive T cells
o Dendritic cells can carry self antigens to secondary lymphoid
organs
o However, many of these semi-mature dendritic cells originate in
places where there are no invaders. Thus, these cells have not
been fully activated by battle cytokines, and do not express the
co-stimulatory molecules needed to activate T cells.
o When a T cell recognizes self antigen presented on the dendritic
cell, but does not receive the required co-stimulation, the T cell
is anergized (neutered) and eventually dies
 Peripheral tolerance
• Some virgin T cells stray out into the tissues, where they may encounter
self antigens that can activate them
• However, these self-reactive T cells do not receive the co-stimulation
needed to activate them. APCs specialize in providing co-stimulation,
but normal cells in tissue do not.
• When a T cell recognizes its cognate antigen presented on a cell, but
does not receive the required co-stimulation, the T cell is anergized
(neutered) and eventually dies
• If a T cell somehow becomes activated by self antigens in the tissues, it
is stimulated repeatedly by the ever-present self antigens. Eventually the
T cell is eliminated by activation-induced cell death (AICD).

Secondary lymphoid organs

- Include lymph nodes, spleen, and mucosal-associated lymphoid tissue (MALT)
- Strategically situated to intercept invaders that breach the physical barriers and enter the tissues
and blood
- Create an environment in which antigen, APCs, and lymphocytes can gather to initiate an
immune response
- Lymphoid follicles
o Found in all secondary lymphoid organs
o Primary lymphoid follicles
 Loose networks of follicular dendritic cells (FDCs) embedded in a sea of B cells
 FDCs function to display antigen to nearby B cells
• Early in an infection, complement-opsonized antigen is delivered to
secondary lymphoid organs. FDCs pick up and retain the opsonized
antigen.
• Later in an infection, antigen opsonized by antibodies can also be
captured by FDCs
• By capturing large numbers of antigens and holding them close together,
FDCs display antigens in a way that can cross-link BCRs on nearby B
cells
• Activated B cells proliferate, turning the lymphoid follicle into a
secondary lymphoid follicle (germinal center)
o Secondary lymphoid follicles (germinal centers)
 As B cells proliferate, they need to be rescued by Th cells. If they are not
rescued, the B cells commit apoptosis.
• Activated Th cells in the T cell areas of the secondary lymphoid organs
migrate to the lymphoid follicle
19
 • CD40L on Th cells plug into CD40 receptors on B cell surface,
providing the necessary co-stimulation.
 In turn, activated B cells restimulate the Th cells
• When B cells take up their cognate antigen, they present the antigen
fragments on class II MHC molecules
• These B cells also express B7 on their surface
• The presented antigen and B7 function to recharge the Th cells
 After proliferation, some B cells become plasma B cells and leave the germinal
center. Other B cells undergo somatic hypermutation to improve their affinity
for their cognate antigen, and can switch the class of antibody that they produce.
- High endothelial venules (HEVs)
o Found in all secondary lymphoid organs except the spleen
o Allow B and T cells to enter the secondary lymphoid organ from the blood
- Lymph nodes
o Function as “dating bars” where T cells, B cells, APCs, and antigen all gather for the
purposes of activation and re-stimulation
 Invaders like bacteria and viruses are carried by the lymph to nearby nodes
 APCs, complement proteins, and antibodies that have picked up foreign antigens
travel to lymph nodes via lymph, to present their cargo
 B & T cells circulate from node to node looking for their cognate antigen
• Cells can enter lymph nodes from the blood via HEVs, or from the
lymph
• Cells can only leave the lymph nodes via the lymph
• There are separate areas in the lymph node for B & T cells
o Passage of lymph
 Incoming lymph  marginal sinus  cortex  paracortex  medullary sinus
 outgoing lymph
 The walls of the marginal sinus are lined with macrophages that serve to clean
and filter the lymph
 HEVs are located in the paracortex
o Role in Th cell function
 If a Th cell passing through the paracortex encounters a dendritic cell presenting
its cognate antigen, it is activated and begins to proliferate. The Th cells then
exit via the lymph, recirculate through the blood, and reenter lymph nodes to be
restimulated.
 Some Th cells move to the lymphoid follicles to rescue B cells, and some Th
cells exit the blood to provide cytokine help to immune cells at the battle site
• Activated Th cells express receptors for a chemokine produced in the
region of the lymph node where activated Th cells and B cells meet.
This causes activated Th cells to be attracted toward B cells needing co-
stimulation.
o Role in killer T cell function
 If a killer T cell passing through the paracortex encounters a dendritic cell
presenting its cognate antigen, it is activated and begins to proliferate. The killer
T cells then exit via the lymph, and recirculate through the blood.
 Some killer T cells reenter lymph nodes via HEVs to be restimulated. Other
killer T cells exit the blood at sites of infection to kill pathogen-infected cells.
o Role in B cell function

20
  If a B cell encounters a follicular dendritic cell presenting its cognate antigen,
and receives co-stimulation from activated Th cells, it is activated and begins to
proliferate in the lymphoid follicle
• Virgin B cells express receptors for the chemokine CXCL13, which is
secreted by FDCs. This causes B cells to be attracted to the area of the
lymph node where the FDCs are displaying opsonized antigen.
• If the B cells encounter their cognate antigen, they express CCR7
receptors for a chemokine produced in the region of the lymph node
where activated Th cells and B cells meet. This causes B cells to be
attracted toward activated Th cells.
 Many B cells exit via the lymph. Some become plasma cells that go to the spleen
or bone marrow to pump out antibodies. Others recirculate through the lymph
and blood, and reenter secondary lymphoid organs where they can proliferate,
undergo somatic hypermutation, and undergo class switching. Still other B cells
go back to the resting state in the spleen or bone marrow to function as memory
cells.
o Lymph nodes that drain sites of infection tend to swell
 Due in part to proliferation of lymphocytes within the node
 Cytokines produced by Th cells recruit additional macrophages which tend to
plug up the medullary sinus. Fluid is retained in the node, causing further
swelling.
- Peyer’s patches
o Examples of MALT
o Adult human has ~200 Peyer’s patches
o Have outgoing lymphatics and HEVs, but no incoming lymphatics
o M cells
 Enclose intestinal antigens in endosomes, and deliver them to tissues surrounding
the small intestine
 Transport only antigens that can bind to the surface of intestinal cells, and thus
have the potential to cause infection
o Once antigen is acquired, Peyer’s patches function similarly to lymph nodes
 The antigen can interact with B and T cells that have entered via HEVs, or it can
travel with the lymph to lymph nodes that drain the Peyer’s patch
o Specialize in turning out Th2 cells and B cells that secrete IgA antibodies
- Spleen
o No incoming lymphatics or HEVs
o Functions as a blood filter
 Everything in the blood can enter the spleen (not just B and T cells)
 Blood enters from the splenic artery and is diverted out to marginal sinuses
 Macrophages lining the marginal sinuses clean and filter the blood
 As they ride along with the blood, T and B cells are temporarily retained
• T cells are retained in the periarteriolar lymphocyte sheath (PALS) that
surround the central arteriole
• B cells are retained in the region between the PALS and the marginal
sinuses
 Filtered blood leaves via the splenic vein
- Lymphocyte trafficking
o Traffic patterns of virgin and experienced lymphocytes are different

21
 o T cell trafficking
 Virgin T cells express cellular adhesion molecules that allow them to visit all
secondary lymphoid organs
• L-selectin on virgin T cell surface can bind to GlyCAM-1 on HEVs of
lymph nodes
• α4β7 integrin on virgin T cell surface can bind to MadCAM-1 on HEVs
of MALT
 Experienced T cells express specific cellular adhesion molecules depending on
where they were activated
• Example: T cells activated in a Peyer’s patch express high levels of α4β7
integrin and low levels of L-selectin
• When activated T cells recirculate, they tend to reenter the same type of
secondary lymphoid organ in which they encountered an antigen. This
maximizes their chances of reencountering their cognate antigen.
 Experienced T cells also carry cellular adhesion molecules that direct them to
exit the blood at sites of inflammation. This enables killer T cells to kill infected
cells and Th cells to provide cytokines.
o B cell trafficking
 Virgin B cells can visit all secondary lymphoid organs, just like virgin T cells
 Experienced B cells do not migrate as much as experienced T cells. They settle
down in secondary lymphoid organs or the bone marrow, produce antibodies, and
let them do the traveling.

Turning off the immune system

- As foreign antigen is eliminated, the level of activation of both the innate and adaptive systems
decreases
- B7 proteins
o In addition to providing co-stimulation to T cells by plugging into CD28 receptors, B7
can also plug into CTLA-4 receptors on the T cell surface
o CTLA-4 ligation represses activation by antagonizing CD28 signaling. B7’s affinity for
CTLA-4 is thousands of times higher than its affinity for CD28.
o Most of a virgin T cell’s CTLA-4 is stored inside the cell. Once the T cell is activated,
more CTLA-4 is moved to the cell surface. Eventually, CTLA-4 outcompetes CD28 for
B7 binding, shutting off the adaptive immune system.
- Regulatory T cells
o When helper T cells out in the tissues are repeatedly stimulated, some of them can turn
into regulatory T cells
o Secrete cytokines which help inactivate the immune system (e.g. IL-10 and TGFβ)
 TGFβ binding reduces the rate of T cell proliferation, makes killer T cells less
vicious, and silences helper T cells
 IL-10 binding blocks co-stimulation of T cells, making it more difficult to
activate T cells
- Many weapons of the immune system are short-lived, and are quickly depleted once the invader
is banished. T cells are an exception, designed to live a long time.
- Activation-induced cell death (AICD)
o T cells which have been repeatedly activated during the battle become increasingly
susceptible to killing by ligation of their Fas proteins

Immunological memory
22
- Innate memory
o Hard-wired and not updatable
o Depends on pattern-recognition receptors that evolved over millions of years to identify
signature structures of common invaders
o All humans have the same innate memory
- Adaptive memory
o Updatable
o B cell memory
 When B cells are activated during the initial response to an invader, 3 kinds of B
cells are generated
• Short-lived plasma B cells
o Produced in lymphoid follicles of secondary lymphoid organs
o Travel to the bone marrow or spleen and produce huge quantities
of antibodies that are specific for the attacker
o Die after a few days
• Long-lived plasma B cells
o Take up residence in the bone marrow
o Continuously produce modest amounts of antibodies
o Provide life-long immunity to subsequent infections
• Central memory B cells
o Take up residence in secondary lymphoid organs
o Serve as stem cells which slowly proliferate to maintain a pool
of central memory B cells and to replace long-lived plasma B
cells
o Can quickly produce short-lived plasma B cells if another attack
occurs
o T cell memory
 After virgin T cells have been activated in response to an initial attack, they
proliferate ~1000-fold
 Memory effector T cells
• Many activated T cells become effector T cells that travel out to tissues
and battle the invader
• After the invasion, most effector T cells die. However, some remain in
the tissues as memory effector T cells, and wait quietly for a subsequent
attack.
 Central memory T cells
• Some activated T cells remain in the bone marrow and secondary
lymphoid organs as central memory T cells
• During a subsequent attack, central memory T cells activate quickly and
proliferate
• Most mature into effector T cells that travel out to tissues
• Some remain as central memory T cells and wait for another attack
o Memory B and T cells are more numerous and easier to activate than virgin B and T cells
o Memory B cells are upgraded versions of virgin B cells
 Instead of making the default IgM class of antibodies, memory B cells can
immediately make the class of antibody best suited to defend against the invader
 Memory B cells have receptors and antibodies that have been fine-tuned during
the initial attack through somatic hypermutation
23
Vaccinations
- Memory helper T cells and B cells can be produced even when an invader does not infect an APC
- For memory killer T cells to be made, the invader must infect an APC
o An effective AIDS vaccine must generate memory killer T cells
- Noninfectious vaccines
o Use killed/disabled pathogens, certain parts of pathogens, or weakened bacterial toxins
(toxoids)
o Can generate memory Th cells and B cells, but cannot generate memory killer T cells
- Attenuated vaccines
o Use weakened (attenuated) pathogens
o Can generate memory Th cells, B cells, and killer T cells
o Can be harmful for individuals with weakened immune systems
o The attenuated virus may mutate inside the recipient to a stronger form, before the
immune system has had the chance to subdue it
- Carrier vaccines
o A single gene from a pathogenic microbe is introduced into a virus that does not cause
disease
o If the engineered virus infects the recipient’s APCs, these cells will produce the
pathogenic microbe’s protein as well as the carrier’s own proteins
o Can generate memory Th cells, B cells, and killer T cells
- DNA vaccines
o Viral DNA is taken up by APCs, which then use the genes to manufacture viral proteins
and display them in class I MHC molecules
o Can generate memory Th cells, B cells, and killer T cells

Immunopathology
- Pathological conditions caused by normal immune response
o Tuberculosis
 TB bacteria taken into the lungs are phagocytosed normally by lung macrophages
 However, TB bacteria can modify the surface of the phagosome so that it cannot
fuse with the lysosome
 After a period of growth and proliferation, TB bacteria burst out of the
macrophage, killing it and infecting other macrophages
 As macrophages die by necrosis, their lysosomal contents damage the lung
tissues and initiate an inflammatory reaction. This recruits other immune system
cells to the area, causing more tissue damage.
o Sepsis
 Kills ~250,000 Americans/year
 Caused by bacteria (most often Gram-negative) that enter the bloodstream and
cause a system-wide immune response
• Gram-negative bacteria have LPS as a component of their cell walls, and
also shed LPS into the surroundings
• LPS activates macrophages and NK cells
• Positive feedback loops amplify the immune response
 TNF secreted by activated macrophages increase the permeability of blood
vessels. Fluid escapes into the tissues, and decrease in blood volume can cause
heart failure (septic shock).
- Diseases caused by defects in immune regulation
24
o Allergies
 Non-allergic people respond weakly to allergens, and produce mainly IgG
antibodies
 Allergic (atopic) people respond strongly to allergens, and produce excessively
large quantities of IgE antibodies
 Mast cells
• On first exposure to an allergen, some people produce lots of IgE
directed against the allergen
• Mast cells have receptors on their surface that can bind to Fc regions of
IgE
• On second exposure to the allergen, IgE already bound to the surface of
mast cells can bind the allergen
• This causes the mast cell to degranulate and release chemicals (e.g.
histamine) into the tissues
• The chemicals increase capillary permeability so that fluid escapes into
tissue. In extreme cases, blood volume can reduce so much that a heart
attack occurs.
• The chemicals also cause bronchoconstriction, making breathing
difficult. In extreme cases, this can cause suffocation.
• Basophils and eosinophils also have receptors for IgE antibodies, and
cross-linking of these receptors can lead to degranulation
 2 phases of allergic reactions
• Immediate
o Caused by mast cells (stationed out in the tissues) and basophils
(recruited from the blood by activated mast cells)
• Delayed
o Caused by eosinophils
o Before an attack by an allergen, there are relatively few
eosinophils present in the tissues or in the blood
o Once an allergic reaction has begun, Th cells secrete cytokines
that recruit eosinophils from the bone marrow
 Susceptibility to allergies
• Atopic individuals have allergen-specific Th cells that are strongly
polarized toward a Th2 cytokine profile, resulting in the overproduction
of allergen-specific IgE antibodies
• Hygiene hypothesis
o During pregnancy, maternal Th cells are biased toward Th2 cells
and away from Th1 cells. This serves a protective function for
the fetus, because maternal killer T cells and NK cells activated
by Th1 cytokines could potentially attack the placenta.
o Placental cytokines also have a strong influence on fetal Th cells.
Bias toward Th2 profile in the mother also causes most humans
to be born with Th cells that are strongly biased toward making
Th2 cytokines.
o Microbial infections in early childhood can elicit a Th1 response,
and thus reprogram the immune system to have a more balanced
population of Th1 and Th2 cells

25
 o In Western cultures, where improved personal hygiene has led to
a decrease in childhood infections, the incidence of allergies to
environmental allergens has increased dramatically
• Regulatory T cells
o Help bias the immune system away from IgE production in
response to allergens
o Th cells in the tissues can be induced to become regulatory T
cells when they are stimulated repeatedly
o Thus, routine exposure to environmental allergens may produce
lots of protective regulatory T cells
o In non-atopic individuals, regulatory T cells represent the
majority of CD4+ T cells that are specific for common
environmental allergens
• The genes a person inherits can make him more or less susceptible to
allergies
o Atopic individuals tend to have particular class II MHC genes
that may be especially efficient at presenting allergens
o Some atopic individuals produce mutant forms of IgE receptor,
which may send unusually strong signals when they are cross-
linked
o Some atopic individuals have mutations in the promoter region
of the IL-4 gene, which may result in increased production of IL-
4
 Treatment
• Glucocorticoid steroids
o Block cytokine production by Th cells  fewer B cells are
activated  total number of antibodies made (all classes) is
reduced
o Can result in increased susceptibility to infectious diseases
• Omalizumab
o Antibodies that can grasp the Fc region of IgE antibodies, and
thus block their binding to mast cells
o Expensive
• Specific immunotherapy
o Only known cure for allergies
o Involves the injection of gradually increasing doses of crude
extracts of allergens until a maintenance dose is achieved. After
several years of regular injections, some patients become tolerant
to the allergens in the extract.
o The injections encourage allergen-specific B cells to switch their
antibody class away from IgE, possibly via the generation of
regulatory T cells
o Autoimmune disease
 Present in ~5% of Americans
 Autoimmunity due to genetic defects
• Autoimmune lymphoproliferative syndrome & Canale-Smith syndrome

26
 o Individuals have genetic defects in either Fas or Fas ligand 
self-reactive T cells cannot be eliminated by activation-induced
cell death
o Massive swelling of lymph nodes, production of antibodies that
recognize self-antigens, and accumulation of large numbers of T
cells in secondary lymphoid organs
 Autoimmunity in genetically normal individuals
• More common
• 3 criteria for autoimmunity
o Individual must inherit and express MHC molecules that
efficiently present a peptide derived from the target self antigen
o Individuals must produce T and B cells with receptors that
recognize a self antigen
o There must be environmental factors (e.g. microbial infections)
that lead to the failure of tolerance mechanisms to eliminate self-
reactive lymphocytes
 Molecular mimicry
• During a microbial invasion, lymphocytes
whose receptors recognize microbial antigens
will be activated
• Sometimes these receptors also recognize
(cross-react with) a self antigen, and an
autoimmune response can result
• Before the microbial infection, the potentially
self-reactive lymphocytes were not activated
either because the affinity of their receptors for
the self-antigen was too low to trigger
activation, or because the restricted traffic
pattern of virgin lymphocytes never brought
them into contact with the self antigen
 An inflammatory reaction must take place in tissues
where the self antigen is expressed. The inflammation
can be caused either by the mimicking microbe itself, or
by another, unrelated infection or trauma.
• T cells activated by molecular mimics still need
to be restimulated out in the tissues, or die of
neglect
• Cells of the innate system secrete inflammatory
cytokines (e.g. IFN-γ, TNF) that activate APCs.
Activated APCs express the MHC and co-
stimulatory molecules needed to restimulate T
cells.
• In addition, inflammatory cytokines can
upregulate class I MHC expression on normal
tissue cells, making them better targets for
destruction by self-reactive killer T cells
• Types of autoimmune diseases
o Organ-specific
 Insulin-dependent diabetes mellitus
27
 • Immune cells attack the insulin-producing β
cells of the pancreas
• Strong genetic component
o Some individuals have a variant gene
for CTLA-4, and are less able to limit
the activity of self-reactive T cells that
recognize β cell antigens
• >90% of β cells are destroyed before symptoms
appear. However, antibodies that bind to β cell
antigens can be detected early in the disease.
 Myasthenia gravis
• Self-reactive antibodies bind to ACh receptors at
neuromuscular junction  muscle weakness and
paralysis
• A poliovirus infection may provide one mimic
that could activate lymphocytes whose receptors
cross-react with the ACh receptor
 Multiple sclerosis
• Inflammatory disease of the CNS initiated by
self-reactive T cells
• Chronic inflammation destroys myelin sheaths,
causing paralysis and defects in sensory inputs
• Strong genetic component
• Virgin T cells cannot cross the blood-brain
barrier, but activated T cells can
• T cells isolated from MS patients can recognize
components of myelin basic protein, herpes
simplex virus, and Epstein-Barr virus
• When individuals are infected with herpes virus
or Epstein-Barr virus, the activated T cells they
produce can potentially cross-react with myelin
basic protein
o Multi-system
 Rheumatoid arthritis
• Chronic inflammation of the joints
• T cells from arthritic patients can recognize
components of a certain cartilage protein and
tuberculosis bacteria
• When individuals are infected with TB, the
activated T cells they produce can potentially
cross-react with the cartilage protein
• IgM-IgG antibody complexes found in the joints
can activate macrophages, increasing the
inflammatory reaction via their secretion of
tumor necrosis factor (TNF)
• Treatment includes antibodies that bind to TNF
and prevent it from working, as well as fake
receptors for TNF
 Lupus erythematosus
28
 • Affects 250,000 people in the USA (90%
women)
• Strong genetic component
• Multiple manifestations
o Red rash on the forehead and cheeks
o Inflammation of the lungs
o Arthritis
o Kidney damage
o Hair loss
o Paralysis
o Convulsions
• Caused by a breakdown in T & B cell tolerance,
that results in production of IgG antibodies that
recognize many self antigens (DNA, DNA-
protein complexes, and RNA-protein
complexes)
• The self antigen-IgG complexes clog organs that
contain filters (kidney, joints, brain, etc.),
causing chronic inflammation
• May involve a defect in activation-induced cell
death, in which lymphocytes that should die due
to chronic stimulation survive to cause the
disease
 Diseases due to immunodeficiency
• Genetic defects leading to immunodeficiency
o Afflict 1 in 10,000 newborns
o Individuals with nonfunctional CD40 or CD40L are unable to
mount a T cell-dependent antibody response
o DiGeorge syndrome
 Essentially all thymic tissue is missing
 Patients lack functional T cells
o Severe combined immunodeficiency syndrome (SCIDS)
 Patients lack functional B and T cells
o Individuals with defective complement proteins have lymph
nodes with abnormal architecture (no germinal centers) and B
cells which mainly produce IgM antibodies
• AIDS
o Affects >60 million people worldwide (>5 million new
infections/year)
o Caused by human immunodeficiency virus-1 (HIV-1)
o Acute phase
 HIV-1 enters human cells, and uses them to proliferate
• Viral RNA is converted to cDNA by reverse
transcriptase
• Viral cDNA is inserted into cellular DNA
• Newly made viruses burst out of each cell, and
go on to infect other cells

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  In the early stages (before the adaptive immune system
kicks in), the number of viruses (viral load) increases
dramatically
 After ~1 week, activated virus-specific killer T cells
cause a marked decrease in viral load
o Chronic phase
 Can last for >10 years
 Viral load remains low, and virus-specific killer T cells
and Th cells remain high (indicating an ongoing effort
by the immune system to defeat the virus)
 As Th cells are killed, their total number decreases.
Eventually there are not enough Th cells left to provide
help to killer T cells, and they decline in number as well
 viral load increases dramatically
 Individual becomes highly susceptible to opportunistic
infections, which can be lethal
o When viral cDNA is inserted into cellular DNA, the virus can
enter a stealthy latent state in which the infected cell cannot be
detected by killer T cells
o Reverse transcriptase is very error prone, and can introduce
mutations that allow newly-made viruses to evade the immune
system. The mutation of HIV-1 is so high that it can effectively
stay one step ahead of killer T cells or antibodies directed against
it.
o HIV-1 binds to CD4, and thus specifically targets Th cells,
macrophages, and dendritic cells. These crucial immune cells
are killed by the virus, or by killer T cells that recognize them.
o HIV-1 can attach to the surface of dendritic cells and be
transported from the tissues (relatively few CD4+ cells) to lymph
nodes (many CD4+ cells)
o HIV-1 that has been opsonized by complement or antibodies is
retained in lymph nodes by follicular dendritic cells. CD4 + cells
can be infected as they pass through the lymph node.

Cancer
- Arises when growth control systems within a cell are corrupted
- Cells can proliferate inappropriately when a proto-oncogene is mutated into an oncogene
- Tumor suppressor genes code for proteins (e.g. p53) that help safeguard against uncontrolled cell
growth
- Cancer cells suffer from high mutation rates that can disrupt growth control systems
- Classification of cancer cells
o Solid tumors vs. blood-cell cancers
 Non-blood-cell cancers (solid tumors)
• Carcinomas
o Cancers of epithelial cells
o Most common
o Include lung, breast, colon, cervical, and other cancers
o Generally kill by metastasizing to vital organs, where they grow
and crowd the organ until it can no longer function
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 • Sarcomas
o Cancers of connective tissues and structural tissues
o Include bone cancer (osteosarcoma) and others
 Blood-cell cancers
• Arise when immature blood cells proliferate continuously without
maturing
• Leukemias
o Immature blood cells fill up the bone marrow and prevent other
blood cells from maturing
o Patient usually dies from anemia (deficit of red blood cells) or
from infections (deficit of immune system cells)
• Lymphomas
o Clusters of immature blood cells for in secondary lymphoid
organs
o Patient usually dies from infections or from organ malfunction
o Spontaneous vs. virus-associated
 Spontaneous
• More common
• Arise when a single cell accumulates a collection of mutations that
causes it to acquire the properties of a cancer cell
• Mutations can result from errors in DNA replication, carcinogens,
radiation, etc.
 Virus-associated
• ~1/5 of all human cancers
• Some viruses produce proteins that can interfere with the proper
functioning of growth-control systems in infected cells
• The viruses decrease the total number of cellular genes that must be
mutated to turn a normal cell into a cancer cell
• Only a small fraction of infected individuals actually get cancer
• The virus or viral genes can usually be recovered from tumors
- Immune surveillance against cancer
o The immune system is designed to preserve tolerance to self (and avoid autoimmune
disease). However, this results in a compromised ability to destroy cancer cells.
o Killer T cells and solid spontaneous tumors
 The trafficking of virgin T cells is such that normally, they would never venture
out into the tissues. Thus, virgin T cells never see tumor antigens expressed in
tissues.
 Even if the virgin T cell somehow ventures out into tissues where it can
recognize the tumor antigen, it still requires co-stimulation by APCs in order to
survive. Because the cells expressing tumor antigens are not APCs, the T cell
would be anergized or killed.
 Even if the virgin T cell somehow manages to break the traffic laws AND avoid
being anergized or killed, the tumor cells mutate at such a high rate that they are
always one step ahead of surveillance by killer T cells
 Thus, killer T cells do not provide serious surveillance against solid spontaneous
tumors
o Killer T cells and cancerous blood cells

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  Because blood cell cancers are found in the blood, lymph, and secondary
lymphoid organs, the traffic patterns of cancer cells and virgin T cells intersect
 Some cancerous blood cells express high levels of B7, and therefore can provide
co-stimulation to the T cells
 Thus, killer T cells provide some surveillance against solid spontaneous tumors
o Killer T cells and virus-associated tumors
 Viruses which only cause acute infections do not play a role in cancer. All
viruses which play a role in causing cancer are able to establish chronic
infections during which they enter a stealthy latent state, invisible to killer T
cells.
 Thus, killer T cells do not provide serious surveillance against virus-infected
cells once they have become cancerous
o Immune surveillance by macrophages and NK cells
 In some circumstances, macrophages and NK cells may provide surveillance
against certain kinds of cancer cells
 Bacille Calmette-Guerin (BCG)
• Cousin of tuberculosis bacterium
• Hyperactivates macrophages
• When injected directly into a tumor, the tumor fills up with highly
activated macrophages that can destroy the cancer
 The abnormal expression of surface molecules on tumor cells may allow
activated macrophages to differentiate between cancer cells and normal cells
 NK cells target cells that express low levels of class I MHC molecules, and
which display unusual surface molecules
 Advantages of the innate immune system
• Unlike killer T cells, macrophages and NK cells are quick acting
• Both NK cells and macrophages recognize diverse target structures, so
the chances of them being fooled by a single mutation is small
• Macrophages are located out in the tissues where most tumors arise, so
they can intercept cancer cells at any stage
• Because NK cells do not need to be activated to kill, NK cells circulating
in the blood may be able to destroy either blood-cell cancers or cancer
cells that are metastasizing through the blood from a primary tumor
 Disadvantages of the innate immune system
• Macrophages need to be hyperactivated before they can kill cancer cells.
If there is no inflammatory reaction at the site of the tumor, macrophages
will remain in a resting state and simply ignore cancer cells.
• NK cells are mainly found in the blood, and are recruited by activated
macrophages and dendritic cells. If there is no inflammatory reaction at
the site of the tumor, NK cells will just continue to circulate in the blood.
 Cancer cells begin to die when the tumor becomes very large, or when they
accumulate mutations that are lethal. Dying cancer cells may provide the signals
required to activate macrophages, which can then recruit NK cells from the
blood.
- Immunotherapy as cancer treatment
o Expensive and not very effective
o Most successful in treating minimum residual disease – cancer cells which remain after
the primary tumor has been removed

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 o Chemotherapy and radiation therapy are most effective against rapidly growing tumors,
where the cells have less time to repair DNA damage. Immunotherapies do not depend
on damaged DNA causing cells to commit apoptosis, so they may be suited to destroying
slow-growing tumors.
o Active immunotherapy
 Based on the idea that the immune system might be able to destroy a tumor, if
only a sufficient number of tumor-specific killer T cells could be mobilized via
physician assistance
o Passive immunotherapy
 The patient’s immune system plays a less active role in combating the tumor
 Physicians do most of the work by removing potential cancer-destroying immune
cells from a patient’s body, engineering these cells to become more potent
fighters, and injecting them back into the patient
- Vaccinations to prevent virus-associated cancer
o Very successful

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