Transcript immune response vaccination

IMMUNE RESPONSE:
INFECTION AND
VACCINATION
Activation of naïve T cells
• Naïve T cells are activated in lymph nodes and spleen.
• Dendritic cells are key antigen presenting cells for naïve T
cells.
• Naïve T cells require MHC/peptide plus antigen-presenting
cell "costimulation" in the form of B7 molecules.
• Only "professional" antigen presenting cells express B7
molecules. And these only express B7 when activated.
• Antigen stimulation without costimulation can lead to loss
of T cell responsiveness and immune tolerance.
How naïve, mature abT cells find antigen
• Antigen transport. Naïve cells are mainly in lymph nodes
and spleen. Dendritic cells transport antigen to draining
lymph nodes, blood borne antigens lodge in spleen.
• T cell entry to lymph nodes. T cells recirculate through
lymph nodes using homing receptors, integrins and
responding to chemokines constitutively produced by
the lymph node stroma. (Parham 6.2-6.3)
• T cell scan of APCs. T cells scan antigen presenting
cells. Interaction is initiated by adhesion molecules.
(Parham 6.4)
• Antigen recognition.
Figure 6-3
T cell entry into lymph nodes from capillaries
Figure 6-3
Figure 6-7
Recognition by T cells of peptide/MHC on dendritic cell leads to
stronger adhesion and a more prolonged interaction.
Diverse outcomes of immune activation of mature abT cells
CD8
CD8
inappropriate
activation
leads to cell
inactivation
naive
CD4
Activation,
proliferation,
differentiation
1
1
2
CD8
killer
CD4
Th1
CD4
Th2
CD4
inappropriate
activation
leads to cell
inactivation
effectors
How are these cell fate
decisions made?
Th1 vs Th2 is defined by
distinctive pattern of
cytokine expression
T cells encountering antigen on non-activated professional
antigen presenting cells become inactivated
inactivated
Figure 6-10
Major professional
antigen presenting
cells.
Costimulation by
signaling through CD28
Appropriate activation
of naïve T cells requires
in addition to a ligand
for the T cell receptor a
second interaction with
CD28. This second
signal is called
"costimulation." Under
many conditions,
dendritic cells provide
this signal during a
primary response.
Special importance of dendritic cells in activating naïve T cells
• It is currently believed that naïve T cells require
activation by dendritic cells, macrophages or other
"professional" antigen presenting cells.
• Dendritic cells are most efficient because they not only
take up and present antigen, but also because they
move efficiently to lymph nodes to encounter naïve T
cells.
• These professional antigen presenting cells provide
peptide MHC complexes along with a critical
"costimulation."
• Costimulation is believed to be a crucial interaction
between the innate and adaptive immune systems that
regulates T cell responses.
Figure 6-1
Immature
dendritic cells in
tissues actively
capture, take
up, and process
antigens.
Upon
maturation,
they migrate to
draining lymph
nodes and
present
antigens to T
cells.
Figure 6-2
Green, MHC
Red, Lysosomes
Dendritic cells
make multiple
contacts with T
cells
Figure 6-12
Activated
Activated Dendritic
cells express B7
molecules
Only activated antigen
presenting cells
express B7 molecules
which are among the
most important
costimulatory signals.
In macrophages and dendritic
cells, innate immune signals
stimulate B7 expression.
Inert
proteins do
not stimulate
B7
expression,
even if they
are foreign.
Figure 6-15
Adjuvant: important component of vaccines
No detectable
antibody response
Ovalbumin
Strong antibody
response
Ovalbumin
+ Adjuvant
Adjuvants work by slowing the release of
antigen, promoting phagocytosis, and providing
inflammatory signals that promote costimulation
Figure 12-4
***
**
**
Active ingredient
N-actylmuramyl-Lalanine-Disoglutamine
(MDP)
MDP is derived from mycobacterial proteoglycan
Figure 6-15
Inert
proteins
given with
adjuvants
can
stimulate a
response.
Diptheria/ tetanus/ pertussis vaccine
Mixture of diptheria toxin (a soluble protein)
tetanus toxin (another soluble protein) and killed
Bordetella pertussis bacteria. The presence of the
bacteria stimulates an improved response to the
toxins (presumably by upregulating B7 expression
by antigen presenting cells). It also leads to more
inflammation and discomfort at the site of injection.
Current adjuvant research is trying to identify
ways of improving the efficacy of vaccine
adjuvants while at the same time reducing
unwanted side effects.
B cells upregulate B7 upon antigen receptor crosslinking
Cross presentation for CD8 priming
•Problem: how can naïve CD8 cells get activated if
activation requires peptide/MHC class I plus
costimulation?
This would require that professional antigen presenting
cells get infected with virus, for example.
•A second problem is that viruses that manage to
suppress MHC class I would evade detection.
•Cross presentation of exogenous proteins on MHC class I
can be specifically carried out by dendritic cells.
Figure 3-19
Dendritic cell "cross presentation" of ingested antigens on MHC class I
There is an important exception to the notion that
class I MHC molecules present peptides generated
within the cytoplasm.
What if the virus doesn’t infect macrophages or
dendritic cells? How do viral peptides get presented
by professional antigen presenting cells so that an
immune response can be induced?
The answer is that dendritic cells, but not other cells,
have a specialized mechanism for shuttling peptides
taken up by endocytosis or phagocytosis into the
MHC class I pathway.
CD36 and
avb5
Take up apoptotic cells for processing within the dendritic cell
Cross presentation = Dendritic
cell, but not other cells, can
take up antigens and shuttle
them into the class I pathway.
This is most efficient when the
antigens are particulate
Provides a mechanism to get
viral and bacterial antigens
into profession antigen
presenting cells.
This induces an immune
response to the offending
pathogens.
Trends in Immunology
22:141-148 (2001)
In some cases, CD8 T cells require T cell help for activation
Failsafe
Note that in almost all cases, two (or more) distinct cell types
must be independently activated in order for a productive
immune response to occur. In all cases, both innate and
antigen-specific stimulus is required.
CD4
1) Ag+MHC Class II
2) B7 coexpressed by APC
1) Antigen specific
2) Innate signals
CD8
1) Ag+MHC Class I
2) B7 coexpressed by APC
1) Antigen specific
2) Innate signals
CD8
1) Ag+MHC Class I
2) CD4 effector Ag+MHC Class II
1) Antigen specific
2) Antigen specific
B
1) Ag:sIg crosslinking
2) CD4 effector Ag+MHC Class II
1) Antigen specific
2) Antigen specific
IL-2 is an
important T cell
cytokine
Figure 6-18
In the absence of appropriate costimulation, T
cells can become inactivated (anergic).
Manipulation of costimulation for therapy
B7
Tumor immunity
Tumors typically express MHC class
I molecules, but fail to provoke an
immune response because of CD4
or CD8 T cell tolerance. Some
tumors do express unique antigens
(such as mutated oncogenes) that
could be used to direct killer T cells,
but they fail to express costimulatory
molecules.
Approaches
•Force expression of B7 molecules in antigen tumor
cells by gene therapy.
•Immunize patients with their own tumors in the
presence of powerful adjuvants.
Concepts
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Naïve T cells encounter antigen in the draining lymph nodes and
spleen, not at the site of infection.
Antigen encounter involves transport of antigen, often by uptake of
dendritic cells followed by their migration.
Dendritic cells are key antigen presenting cells for naïve T cells.
Other important professional antigen presenting cells are
macrophages and B cells.
Naïve T cells require peptide/MHC plus costimulation.
A major source of costimulation is B7 expressed by activated
professional antigen presenting cells.
B7 expression by dendritic cells and macrophages is often
stimulated by innate immune ligands.
Encounter of antigen in the absence of costimulation leads to
tolerance. And this is a major pathway of self-tolerance to
peripheral antigens.
Crosspresentation of exogenous antigens on MHC class I
molecules is carried out by dendritic cells, but no other cells.
Inducing costimulation is an important aspect of vaccine adjuvants.