Adaptive Immunity
Afro-ADVAC 2021
Bobby J. Cherayil, MD,
Mucosal Immunology and Biology
Research Center,
Massachusetts General Hospital.
Division of Medical Sciences,
Harvard Medical School,
Boston, Massachusetts, USA
cherayil@[Link]
The protective action of most licensed
vaccines involves antibodies
The antibodies must
• Have broad functionality (help to eliminate
the target microbial antigen by multiple means)
• Have high affinity for the target antigen
• Continue to be produced long after vaccination
Antibodies originate from activated
B lymphocytes as part of the adaptive
immune response
Antibodies are secreted
forms of the BCR
B cell receptor (BCR)
for antigen
Naive B cell Clone of activated Plasma cells Antibodies
B cells Immunoglobulin (Ig)
Antibodies can be of different varieties or isotypes
IgM IgG IgA
m g a
IgE IgD
Minor isotype
Function not
clear
e d
Isotype switching
• During the course of the immune response
different antibody isotypes are generated
by a process called isotype switching.
• Since different isotypes are capable of
different functions, isotype switching
facilitates generation of an antibody
response with broad functionality.
• The specific isotypes that are produced
are influenced by local cytokine concentrations.
Different antibody types have different functions
that help to protect against/eliminate the antigen
1) Neutralization: All antibodies 4) Antibody-dependent cell-mediated
cytotoxicity (ADCC): IgG
NK cell
2) Opsonization: IgG
5) Mast cell activation: IgE
Phagocyte
Mast cell
3) Complement activation: IgM, IgG
6) Protection of mucosa: IgA, IgM
Mucosal epithelium
Lumen
Somatic hypermutation & affinity maturation
During the immune response, point mutations are
introduced into the antigen-binding regions of the
antibody – somatic hypermutation
Point mutations
Some of the mutations alter affinity of binding for the
target antigen. As the response progresses, B cells
capable of producing antibodies with higher affinity for
antigen are selected for continued proliferation –
affinity maturation
The antibody response leads to the
generation of a population of long-lived
memory B cells and plasma cells
Long-lived
Memory
plasma cell
B cell
Extended lifespan Extended lifespan
Enhanced responsiveness Continuous production of
Circulate through blood antibody
and peripheral tissues Resident in bone marrow
How are B cells activated?
• T-independent B cell activation
• T-dependent B cell activation
T-independent activation
Multivalent
antigen
(polysaccharides, Cross-linked
lipids) BCR
Strong
activating
signals
Proliferation &
Differentiation
Short-lived
plasma cells
IgM antibodies
T-dependent activation
Ag
(protein)
B cell
Helper
T cell (Tfh)
T-dependent activation
Ag
(protein)
B cell
Helper
T cell (Tfh)
T-dependent activation
Ag
(protein)
MHCII
B cell
Helper
T cell (Tfh)
T-dependent activation
Ag
(protein)
MHCII Cytokines
B cell
Helper
CD40 CD40L T cell (Tfh)
T-dependent activation
Proliferation &
Differentiation
Isotype switching
Ag IgG, IgA, IgE
(protein) Affinity maturation
Memory
MHCII Cytokines
B cell
Helper
CD40 CD40L T cell (Tfh)
What type of B cell activation is optimal
for a good vaccine response –
T-independent or T-dependent?
What type of B cell activation is optimal
for a good vaccine response –
T-independent or T-dependent?
Vaccines should facilitate
T-dependent B cell activation
Promoting T cell-dependent B cell activation
during vaccination
Not usually a problem for protein antigens.
Non-protein antigens (e.g., carbohydrate) must
be coupled to a protein “carrier” containing a
suitable peptide epitope for presentation to T cells.
Antigen with
B and T epitopes
Protein Carbohydrate Peptide
There’s a catch.....
• Before a T cell can provide help to
a B cell, it must itself be activated by
the same antigen that is presented
by the B cell
• B cells themselves cannot activate
naive T cells
.....So, in order for a vaccine to promote
T-dependent B cell activation, it must
activate T cells to respond to the
antigen presented by the B cell
Most T cells are activated by, and respond to, only
proteins.
The proteins have to be converted into short
peptides.
The peptides have to be displayed on a cell surface.
These requirements imply that an antigen presenting
cell (APC) must be involved in activating T cells. One
of the best types of APC is the dendritic cell (DC),
which is resident in most tissues.
Antigen must be broken down and presented by an
APC before T cells can recognize them
TCR CD28
APC
Antigen must be broken down and presented by an
APC before T cells can recognize them
TCR CD28
APC
Antigen must be broken down and presented by an
APC before T cells can recognize them
TCR CD28
APC
Antigen must be broken down and presented by an
APC before T cells can recognize them
TCR CD28
MHC
APC
Antigen must be broken down and presented by an
APC before T cells can recognize them
Signal 1
TCR CD28
MHC
APC
Furthermore, T cells will respond to the antigen only if
the APC has been previously stimulated via a
Pattern Recognition Receptor (PRR)
Signal 1
TCR CD28
MHC
APC
PRR
MAMP/DAMP
(Activation of
innate immunity)
Furthermore, T cells will respond to the antigen only if
the APC has been previously stimulated via a
Pattern Recognition Receptor (PRR)
Signal 1
TCR CD28
Co-stimulatory
MHC
molecule
APC
PRR
MAMP/DAMP
(Activation of
innate immunity)
Furthermore, T cells will respond to the antigen only if
the APC has been previously stimulated via a
Pattern Recognition Receptor (PRR)
Signal 1 Signal 2
TCR CD28
Co-stimulatory
MHC
molecule
APC
PRR
MAMP/DAMP
(Activation of
innate immunity)
Furthermore, T cells will respond to the antigen only if
the APC has been previously stimulated via a
Pattern Recognition Receptor (PRR)
Signal 2 Proliferation
Signal 1 Signal 2
Signal 1
TCR CD28
Co-stimulatory
Co-stimulatory
MHC
molecule
molecule
APC
PRR
PRR
MAMP/DAMP
(Activation of
innate immunity)
Furthermore, T cells will respond to the antigen only if
the APC has been previously stimulated via a
Pattern Recognition Receptor (PRR)
Signal 2 Proliferation
Signal 1 Signal 2
Signal 1
TCR CD28
Co-stimulatory
Co-stimulatory
MHC
molecule
molecule
APC
PRR Differentiation
PRR
MAMP/DAMP Cytokines
(Activation of (Signal 3)
innate immunity)
Effector functions,
including helping B cells
A good vaccine
Must contain a B cell antigen to stimulate
antibody production.
If the antigen is not a protein, it should be
coupled to a protein carrier to promote T
cell-dependent B cell activation.
Must contain a MAMP or DAMP to stimulate
innate immunity (adjuvant).
Activated T lymphocytes differentiate
into different types of effector T cells
Naive T cell Clone of activated T cells Effector T cells,
including various
helper T cells
Effector T cells eliminate antigen/infection, in
part by interacting with othe immune cells
CD4+ effector T cells
Anti-microbial
Th1, Th2,
Th17 function
Antibody
Tfh production
Regulatory
T cell Inhibition of
(Treg) other immune cells
CD8+ effector T cell
Cytotoxic Killing of neoplastic
T cell or virally infected
(CTL) cells
Memory Memory
T cell T cell
(central) (effector)
Effector T
cells
Plasma cells
Long-lived
Memory
plasma cell
B cell
Memory lymphocytes are responsible
for the prime-boost effect seen
in vaccination
Second exposure
Lymphocyte response
to same antigen (boost)
Initial exposure
to antigen (prime)
Time
Naive Memory
lymphocytes lymphocytes
Questions?
