Adaptive Immunity

Someone inhales an airborne

bacterium and the infection
overwhelms their innate response.
What next?
Overview of Major host Defenses
HOST DEFENSES
Innate Adaptive
Non-specific Specific
Present at Develops as the
birth need arises
Fast Develops
No memory throughout life
Slower
Memory
 2 Branches of Adaptive immune
Response
Cell Mediated Humoral
Immunity Immunity
cytotoxic T- B lymphocytes
lymphocytes antibody
activated proteins
macrophages
Eliminates Eliminates
intracellular extracellular
pathogens pathogens
Who are the major cellular players
in the Adaptive immune
response?

Lymphocytes
B cells (plasma, memory)
T cells (helper, cytotoxic, memory)
How do the B and T lymphocytes
recognize pathogens?

B and T cells have receptors that

recognize antigen (B cell
receptor) or parts of antigen (T
cell receptor)
Where do lymphocytes develop and
where do they encounter antigen?
 Lymphoid Organs and tissues
Classified as primary and secondary

Primary lymphoid organs: sites of

lymphocytic origin and maturation
oThymus
oBone marrow
 Secondary lymphoid organs/tissues :
sites where Tonsils (MALT)

lymphocytes encounter Thymus

Axillary
antigen lymph MALT in breast
node
oLymph nodes Spleen

GALT
oSpleen Inguinal lymph
node
oClusters of lymphoid Bone
tissue that appear in marrow
mucosal surfaces Lymphatic
vessels
(MALT) and in the gut Primary
(GALT) lymphoid
organs
 The Development of Lymphocytes
Bone marrow 1. Release of
immature cells
B cells T cells

Bone 2.Differentiation
and maturation Thymus
marrow
in separate sites
Ig T-cell
receptor receptor
B cell T cell
3. Expression
of cell 4. Migration to lymph
receptors nodes and other 2nd
lymphoid organs
 Lymphocyte Development Terms

oNave lymphocytes: have antigen receptors,

but have not yet encountered the antigen to
which they are programmed to respond
 Lymphocyte Development Terms

oActivated lymphocytes: have bound antigen

to their antigen receptor and have received a
co-stimulatory signal and therefore are able
to expand and differentiate into effector and
memory cells
 Lymphocyte Terms
o Effector lymphocytes: short-lived descendants of
activated lymphocytes, armed with the ability to
carry out a specific immune function (i.e. secrete
antibodies, secrete cytokines, kill infected cells,
etc.)

o Memory lymphocytes: long-lived descendants of

activated lymphocytes; can quickly become active
effector lymphocytes upon second exposure to an
antigen
 T cell clonal Selection and Expansion
Activated CD8+
Antigen T cell
Thymus (processed)

Co-stimulatory
Nave CD8+ T signal
cell
Memory
CD8+ T cell

Nave CD4+ T
Effector CD8+ T
cell cell
(Cytotoxic T cell)
Thymus Th1 cell
Effector CD4+ T cell
(Helper T cell)
Th2 cell
Nave CD8+ T
cell
Antigen
(processed)

Co-stimulatory Memory
Nave CD4+ T
cell signal CD4+ T cell
Activated CD4+
T cell
B cell Development
 Effector
EffectorCell
CellsTypesMemory Cells

T Th1 (T helper 1) Memory T

lymphocytes cells cells
Th2 (T helper 2)
cells
B Plasma cells Memory B
lymphocytes cells
Lymphocytes recognize antigen but
what are antigens?
 Antigen
Antigen: a foreign
substance recognized by
a BCR, TCR or antibody Antigens Are
Unique to each Like Name
Tags or IDs
microbe or non-
infectious foreign
substance
Antibody
generator
 Antigens
Can be:
Proteins
Polysaccharides
Conjugates of lipids with
Proteins
polysaccharides
 Haptens
Hapten too small, lack
immunogenicity
If hapten is coupled to carrier
protein, immune response can be
induced
 Epitopes
Part of antigen thats recognized by a BCR or TCR
or Ab
 Question
Which of the following is the most
immunogenic (ie which elicits the strongest
immune response)?

A. Single stranded DNA

B. Self (host) protein
C. Piece of plastic
D. Fungal cell
E. Bacterial pilus protein
A whole organism has multiple
antigens with multiple epitopes
 What makes a good antigen?

Large size (more epitopes)

Complexity/ heterogeneity

Proteins generally elicit strong response

Polymers (ie polysaccharides and
nucleic acids) elicit weak response
Lipids are haptens
How do lymphocytes recognize
antigen?
Antigen Recognition

2 antigen binding A single antigen

sites binding site
 Antigen Recognition by B Cell and
T cell Receptors

B Cell Receptor T cell Receptor

Binds free soluble Binds processed
antigens antigens that are
presented to them by
MHC receptor; dont
bind soluble antigen
 B Cell and T cell Receptors

Each B cell and each T cell expresses a

unique BCR or TCR that recognizes one
single epitope

Population in body responds to >100

million epitopes but there arent 100
million receptor genes!
 TCR and BCR Diversity is Generated
by Gene Rearrangement
The gene loci consists of families of gene
segments
Each set of segments contains alternative
versions of parts of the receptor protein
During B and T cell development, segments of
genes are randomly cut and spliced by genetic
recombination to assemble a functional receptor
gene
Rearrangement of gene cassettes that
encode BCR and TCR
 Negative Selection of Auto Immune
Clones
Each genetically different type of
lymphocyte expresses a single specificity
for a specific antigen

Lymphocytes that react with self antigens

(auto-immune) undergo apoptosis (negative
selection)
Negative Selection of Auto Immune
Clones
Genetic recombination
Primary T and B cell Response has
2 major phases

1. Selection and activation of nave

lymphocytes, followed by expansion and
differentiation into effector cells

2. Execution of the effector function

 Selection, Activation and
Expansion
o Selection: Upon entry into immune system,
each antigen or processed antigen is recognized
by (ie selects) a genetically distinct lymphocyte
with the right receptor
o Activation: Signals from another cell are
usually needed
o Expansion: upon activation, the lymphocyte
proliferates and differentiate into a larger
population of identical cells (ie clones) that can
react to that antigen
Clonal Selection and Expansion
After a T cell clone is selected and
expands, what does it do?
 CD4+ T cell Function
Helper T cells
2 subtypes: Th1 or Th2 cells
Helper cells secrete cytokines that
activate other cells of the immune
response
 CD4+ T cell
Function

IFN-g activates
macrophages

IL-2 activates IL-4 and IL-5

CD8+ T cells activate B cells
 CD8+ T cell Function
Cytotoxic T cells (CTL)
Destroy infected cells by secreting granzymes into
the target cell
Target cells undergo apoptosis (cell suicide)
Are effective against intracellular pathogens
particularly viruses

Infected
cell

Tc
Tc cell

Perforin Granzyme

Perforin
complex (pore)

Granzymes activate
cell suicide enzymes

Virally infected cell

Part 2 of Adaptive Immunity: Antigen
Presentation
 Antigen Recognition by T cells

T cells require antigens to be processed and

presented to them by antigen presenting
cells
o ie T cells only recognize short fragments of
antigens (peptides of about 8-25 amino
acids)
Professional Antigen Presenting Cells
(APCs)

1. Macrophages
2. Dendritic cells
3. B cells
 Professional Antigen Presenting Cells
(APCs)
These specialized cells internalize antigen by
phagocytosis or endocytosis and then express
parts of the antigen on their cell surface via MHC
receptors

These cells are distinguished by two properties:

1.Express MHC class II receptors

2.Provide co-stimulatory signals necessary for

activation of T-cells
 Dendritic Cells
Link between innate and adaptive (along
with macrophages)
Migratory cells that recognize pathogens
nonspecifically (PAMPS)
Carry antigen to lymph system
Process and present antigens to T cells
Deliver a co-stimulatory signal to interacting
T cells
Strongest initiator of T cell
activation
Dendritic Cells
 Antigen Presentation
Two types of MHC receptors

1. MHC I present to
CD8T cells
cytotoxic T cells
MHC I MHC II

2. MHC II present to CD4+ T cells

helper T cell
 Major Histocompatibility Complex
MHC Class I Receptor
Receptors found on all nucleated cells (ie, not RBCs)
Bind protein fragments (peptides) generated mainly
from degradation of cytosolic proteins by the
proteasome
Present antigens that originate within the cell
(endogenous antigens):
host proteins (self proteins)
intracellular pathogens ( ie all viruses, a few
bacteria) (nonself proteins)
Present the processed antigen to CD8+ T cells
Major Histocompatibility Complex
MHC Class I Receptor
MHC Class I
Receptors
 MHC Class II Receptors
Receptors found on professional antigen
presenting cells
Note that APCs also express MHC class I
receptors
Bind peptides generated by lysosomal enzymes

Antigens that are presented are exogenous

(originate outside of the cells)
ie most bacteria, toxins, fungi

Present the peptides to CD4+ T cells

MHC Class II Receptors
MHC Class II
Receptors
Overview of Antigen Presentation to
T cells
 Question

Which type of molecule is responsible for

presenting an exogenous antigen on the
surface of the appropriate cell?
A. TCR
B. MHCI
C. MHCII
D. CD4
E. CD8
 Question
Where in the body do APCs go to
present endogenous antigens to
cytotoxic T cells?
A. lymph nodes
B. thymus
C. liver
D. bone marrow
Where does Antigen Presentation Occur?
Secondary lymphoid tissue
 Question
Samantha Johnson has bare lymphocyte syndrome due to
a lack of Class I MHC expression. Only about 150 cases of
this disease have been documented in the world. She
received 2 bone marrow transplants 24 years apart at
Childrens Hospital of Wisconsin. This disease would be
expected to result in an inability of APCs to
 Question
Draw the MHC Class I antigen
presentation pathway.
Your model should show MHC I
antigen presentation from the point of
pathogen entry into host cell to the
point of T cell activation.
Label any structures you draw
Draw arrows to indicate relationships
and label the arrows with words to
describe the relationships.
 Question
Samantha Johnson has bare lymphocyte
syndrome due to a lack of Class I MHC
expression. This disease would be expected
to result in an inability of APCs to
A. Process endogenous antigen for
presentation.
B. Bind to any T cells in the lymph node.
C. Activate any CD4 T cells.
D. A and C are correct
E. A and B are correct
Part 3 of Adaptive Immunity: T and B
cell Activation
 Activation of T cells
1. Requires an interaction between TCR
complex-coreceptor (CD4 or CD8) and the
cognate peptide presented in the context
of MHC II (CD4+ T cells) or MHC I (CD8+ T
cells) on APCs
2. Requires a co-stimulatory signal from the
(mediated by CD28)
3. Requires IL-2 to expand and differentiate
into effector and memory T cells
Interleukin 2 (IL-2) and T cell Activation
A type of cytokine produced by T cells
The co-stimulatory signal from the APC is
required for T cells to be able to synthesize
and secrete IL-2
Necessary to induce proliferation and
differentiation of activated T cells
Activation of T cells
Interleukin 2 (IL-2) and T cell Activation
A type of cytokine produced by T cells
The co-stimulatory signal from the APC is
required for T cells to be able to synthesize
and secrete IL-2
Necessary to induce proliferation and
differentiation of activated T cells
Activation of Helper T cell response
Activation of
Helper T cell
response
Dendritic cell

MHC II

CD4 Epitope

TCR

CD4+ T cell

Immunological synapse
 Once T helper cells are activated

IFN gamma
Th1 cells Macrophages
IL-2
CD8+ T cells

IL-4, 5
Th2 cells B cells
 Activated Macrophages
phagosome will be more efficiently fused to
the lysosomes
production of highly reactive and
microbicidal molecules:
- oxygen radicals
- nitric oxide
- proteases
Defense against intracellular bacteria
 Question
Which type of lymphocyte is
responsible for virus-infected host
cells?

A.B lymphocyte
B. helper T cell
C. cytotoxic T cell
D.plasma cell
Activation of Cytotoxic T cell Response
 Activation of
Cytotoxic T cell
Response
Dendritic cell

MHC I

CD8 Epitope

TCR

CD8+ T cell

Immunological synapse
 B cells

B cells recognize antigen directly

When B cells are activated, they
differentiate into plasma cells
Plasma cells make and secrete antibodies
(secreted Ig)
Effector Function of B cells

(secreted Ig) Surface Ig

 Question
When antigens activate B cells, they clone and
give rise to _ cells and __ cells.

A. Antibody / Plasma
B. Antibody / Memory
C. Memory / Helper
D. Antigen Presenting / Antibody
E. Plasma / Memory
 B cell Activation-2 mechanisms
B cell receptor

Endocytose the
B antigen, process it
Bacterium
and present on
MHCII to TH2 cells
A

Some antigens Strong activation

crosslink BCR T

Weak activation T
 T-independent B cell Activation

Rare, highly repetitive antigens

B cells are weakly stimulated to make
IgM antibodies, independently of TH
cells
Few-No memory cells produced
T-independent antigens are rare
highly repetitive molecules
T- independent B cell Activation
Polysaccharide
(T-independent antigen)

Epitopes

B cell
receptors

Crosslinking/ capping serves as a co-

stimulatory signal to activate the B cell
 T-dependent B cell Activation
B cells present antigen on their MHC II to
TH2 cell
TH2 cell produces cytokines that strongly
activate the B cell
Such B cells can undergo class switching
to make antibodies other than IgM
Most antigens are T-dependent antigens
 T-dependent Activation
Activated TH2 cell
CD4 receptor
BCR binding to
antigen 1st signal
MHCII

IL4 and IL5

B cell B cell TH2 cell delivers
receptor cytokines, IL4 and
IL5 2nd signal
 Repertoire of Th cells (CD4 cells)
Th cell

T-dependant CD4
TCR

Epitope
CD4
CD28

Activation
TCRs CD80
MHC II
APC (or
CD86)
Antigen
APC
presentation
for Th activation
and cloning

Differentiation of
Th into Th2 cell

CCR3
Th cell clones
CCR4
IL-4
Th2 cell
Clonal
MHC II selection
proteins of B cell
Th2 cell

Th2 cell TCR

CD40L
Epitope

MHC II
CD40
IL-4
B cell
Repertoire of B cells

Activation of
B cell BCR

Clone of
plasma
cells

Memory B cells
Antibodies
Cell-mediated and Humoral responses of
adaptive immunity
Dendritic cell Innate immunity

Activates T cells that

Activation bind antigens
representing danger
Naive B cell Naive CD4+T cell Naive CD8+T cell

Proliferation
and
differentiation Plasma cells TH cells Tc cells
Produce Deliver Deliver death
antibodies cytokines packages

Effector
action &
consequence Antibodies Antibodies bind Macrophage that Macrophage with Infected
Infected self
antigen has engulfed increased killing powerself cell cell undergoes
invaders
Adaptive immunity Adaptive immunity apoptosis

(humoral) (cell-mediated)
 Question
A patient infected with HIV (human
immunodeficiency virus) becomes severely
immunocompromised. This is because HIV
infects and destroys CD4+ T cells. Low CD4+ T
cell count would result in an inability to fight off
infections by which of the following?

A.RNA viruses
B.Extracellular bacteria
C.Intracellular bacteria
D.Fungi Why?
E.All of the above
 Immune Response to an
intracellular pathogen
No organism can be wholly intracellular at all times: if it is
to replicate successfully, transmission must occur between
the host's cells, and this inevitably involves some exposure
to the extracellular environment.

As far as the host is concerned, this extracellular phase in

the development of the pathogen provides an opportunity
to control infection through defense mechanisms such as
phagocytosis (and presentation on MHC II), antibody and
complement

Alternatively an APC can engulf dead parts of viruses and

present on MHCII
 Activating a Cytotoxic T Response to an
intracellular pathogen (ie a virus)

Dendritic cell

Cytotoxic T cells
Part 4 of Adaptive Immunity:
Antibodies and the Memory
Response
 Antibodies are secreted
Immunoglobulin Proteins (Ig)

Antibodies are effective against extracellular

pathogens, such as bacteria, or virus that
has budded from the cell
 Immunoglobulin Structure
Antibodies are heterodimers
2 identical light chains

2 identical heavy chains

Disulfide bonds join heavy, light chains and

two halves

First 110 aa of amino-terminal end of heavy

and light chain vary depending on antibody
specificity. Other part remains constant
Immunoglobulin Structure
 Immunoglobulin Structure
V= variable

C= constant
Each Antibody Recognizes A Specific
Antigen
VDJ Gene Rearrangement to generate Ig diversity
 What do antibodies do?

Antibodies circulate through blood

and lymph, ignoring all antigens
except for its specific target antigen

When an antibody finds its antigenic

match, it binds to the antigen and
initiates several events that destroy
the targets
 Antibody Function
Bacteria
Agglutination
Crosslink antigen to
reduce the number
of infectious units to
be dealt with

Causes
Complement
inflammation and
cell lysis Fixes and
activates
complement
Bacterium
 Antibody Function
Opsonization
Phagocyte Coating antigen with
antibody enhances
phagocytosis

Neutralization
Virus Blocks adhesion of
Toxin bacteria and viruses
to mucosa
Bacterium
Blocks attachment
of toxin
 Antibody Class
5 different heavy chain constant
regions
IgM
IgG
IgA
IgD
IgE
Amino acid sequence in the constant
region of the heavy chain determines
the Ig class
 Question
The immune system is capable of generating
responses against a wide variety of invaders. Antibody
diversity is key to long-lasting protection against these
diverse populations. The picture below shows a
typical antibody molecule.
Which regions are responsible for the diversity of the
antibody repertoire?
A D
A C
B
C
D B
5 Immunoglobulin (Ig) Classes

Found in
secretions
 IgM

Monomeric IgM
Disulfide
expressed on B cells bond
Secreted is pentameric
1st class produced in
primary response J chain
Activates complement
Very good at
agglutination
 IgG
Most abundant Ab in
serum
Crosses placenta
Opsonization; Activates
complement; Neutralize
toxins and viruses
 Other Ab Classes

IgA IgD IgE

In secretions Makes up a very Makes up a
(mucus, tears, small very small
breastmilk, saliva) proportion of proportion of
Protects mucosal total serum total serum
surfaces antibodies antibodies
Expressed on B Lysis of
cells as surface parasitic
Ig functions worms
as a BCR
Immunoglobulin Class Switching
 Immunoglobulin Class Switching

Class switching increases the number of

different functional types antibody
molecules without altering the antigen
specificity.
 What happens when a host is
exposed to the same pathogen a
second time?
Memory Response

A larger population of
sensitized plasma cells are
ready to respond
 Memory Response

A larger population of
sensitized plasma cells are
ready to respond
 Memory Response

Significantly faster, more effective than

primary
Pathogens usually eliminated before causing
harm
Note: Vaccination exploits this natural
phenomenon
 Memory B cells
Memory B cells generated from the primary
response differentiate into plasma cells
without needing direct contact to Th2 cell so
they get activated much quicker

Memory plasma cells secrete low levels of

IgG continuously
 Memory B cells

Central Memory B Memory plasma cells

cells
2nd exposure
IgG

Effector Plasma cells

 Antibody Response to
Second Exposure
Memory B cells have already undergone
class switching
Produce IgG antibody without having to
first make IgM and then class switch
IgG is antibody of memory

Both the affinity and amount of antibody

increase with repeated exposure
Both the amount of
antibodies and the
antibodies affinity
for antigen increase
with repeated
exposure

Immunization=
exposure to antigen
 Memory T cells

Central Memory
Central Memory
CD4+ T cells
CD8+ T cells
2nd exposure Dont need IL2
from TH1

Helper T cells Cytotoxic T cells

Memory Response is Faster and more
Effective

Person is
immune= no
disease
 Question
Imagine you are F
exposed to

Antibody titer
Pathogen A on day

in serum
1. You recover and
22 days later, you B E
A C
become exposed to
Pathogen A again
as well as another
D
pathogen,
Pathogen B.
Time (days)
Which line on the graph represents the amount
of IgG to Pathogen A after the second
exposure?
 Question
How is a secondary immune response
different from a primary immune
response?

A. It is slower, but more effective.

B. It is faster, but less effective.
C. It is faster and more effective
D. There is no difference.
Fitting the Adaptive Response all
Together
 Immune Response to Different Types of
Pathogens
Cell meditated immunity Humoral immunity
Example viruses Intracellular Most bacteria and
pathogens bacteria (ie fungi
Mycobacterium
tuberculosis)
Location Cytosol Within Extracellular fluid
macrophages
Antigen Peptide: MHCI on Peptide: MHCII Peptide: MHCII on
Recognition infected cell on infected specific B cell
macrophage

Effector T Cytotoxic T cell TH1 TH2

cell
Effector Killing of infected Activation of Activation of specific
Action cell infected B cell to produce
macrophage antibodies
Overview of the Immune Response