Download Adaptive immunity

Medi 4318
Introduction to host defenses
Ahmad Sh. Silmi
Rm 326 Admin. Building
[email protected]
Office hours: Every week Sun &Tues 11:00 to 12:00.
What are host defenses?
What are the reasons for host defenses?
• Defense against infections.
• Defense against toxins.
• Defense against internal dangers
(cancer, bad pregnancy).
• Regulating defenses: autoimmunity
and pregnancy.
What are the range of mechanisms called
host defenses?
Innate defenses: A broad range of mechanisms that don’t
require selection of cells to secrete or kill specific things (usually
ready instantly or within a few hours).
Adaptive immunity: Selection of cells that secrete or kill.
Requires DNA rearrangements and takes about a week.
Have persistent memory.
Why Differentiate between the Innate and
Acquired Immunity ?
Innate Immunity
• Characteristics:
– Universal
– Rapid
– Lacks memory
– Non specific but ...
Acquired Immunity
• Characteristics:
– Not universal
– ‘Slow’ to develop
– Possesses memory
• Specific but….
– ‘Plays to the tune of
the Innate immune
system’
Both innate and immune defense cells are generated in
bone marrow (or at least start there).
* Mostly
innate
defense
cells
*,*
*
*
*
*
*
*
* Mostly
*,* adaptive
immune
cells.
*
*
*
*
Kuby Fig 2.2
Adaptive immunity is all about generating
functional lymphocytes (B and T).
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node,
spleen, and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Function of mature cells (entire body)
A B lymphocyte has a single kind of BCR which binds only
one type of antigen.
B cell receptor (BCR)
B lymphocyte
Antigen
A T lymphocyte has a single kind of TCR that
recognizes only one kind of antigen.
Antigen
Antigen presenting
cell (APC)
MHC
Antigen (a bit of it)
T cell receptor
T lymphocyte
Adaptive immunity is all about generating
functional lymphocytes.
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node,
spleen and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Function of mature cells (entire body)
How and where is cellular diversity generated?
I. B lymphocytes.
Bone marrow is where B progenitor cells become mature B cells
and migrate to lymph nodes and spleen looking for antigen.
Bone marrow is the primary lymphoid organ for B cells
How and where is cellular diversity generated?
II. T lymphocytes:
Pre-T cells (no TCR)
migrate from bone marrow
to the thymus where they
rearrange DNA.
Within the thymus the pre-T cells
mature into T cells by rearranging
their TCR DNA and generate about
107 cells (each with one copy of
unique TCR DNA) per day, then exit
looking for that antigen.
This process is antigen-independent.
Thymus is the primary lymphoid organ for T cells.
A question for votes:
Where and how is B lymphocyte diversity
generated?
A. In its primary lymphoid tissue, the thymus.
B. By generating new DNA sequences in every B cell.
C. In bone marrow by rearranging existing DNA.
D. In spleen by eliminating cDNA.
Adaptive immunity is all about generating
functional lymphocytes.
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node,
spleen and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Function of mature cells (entire body)
The lymph nodes and spleen are secondary lymphoid organs
Naïve T cells
Naïve B cells
(from thymus through blood)
(from bone marrow through blood)
lymph nodes
or spleen
Antigen (either through
lymph ducts or blood)
If Antigen not
found, the naïve
B and T cells recirculate and die.
If Antigen is
found, the naïve
B and T cells
survive and clonally
expand in the
secondary lymphoid organs.
Adaptive immunity is all about generating
functional lymphocytes.
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node,
spleen, and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Function of mature cells (entire body)
A B cell has a single kind of BCR which binds only
one type of antigen and can clonally expand and
mature into plasma cells that will secrete the
BCR (Ig) which will bind that antigen.
immunoglobulin
B lymphocyte
BCR
clonal
expansion
B memory
cells
Plasma cell
Clonal expansion of T Lymphocytes
A single T lymphocyte
Antigen
Many T lymphocytes
preCTL
TCR
MHC
Antigen (a bit of it)
T cell receptor
TCR
Clonal
Expansion
T lymphocyte
T helper cell
Adaptive immunity is all about generating
functional lymphocytes.
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node,
spleen, and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Functional mature cells (entire body)
Functional B lymphocytes
BCR
immunoglobulin
rapid clonal
expansion
Memory B lymphocytes
Both plasma cells and memory B cells
are present in all the Ig subclasses:
IgM, many kinds of IgG, IgA, IgE.
Plasma cells
Functional T lymphocytes
preCTL
TCR
TCR
T helper cells.
TDTH cells
When mature, these cells leave the
secondary lymphoid organs, enter the
blood steam and home to where
they find their antigen.
TCR
Clonal expansion also
produces memory cells
of both types. These
memory cells
recirculate and
can be
reactivated by
exposure to
antigen in secondary
lymphoid tissue.
T memory cells (both types)
A question for voting:
What does the term clonal expansion mean?
A. A stem cell is triggered to proliferate to form
a clone of progeny cells.
B. A naïve B cell meets its antigen and proliferates
to produce lots of progeny cells.
C. A T memory cell meets its antigen on an APC in
a secondary lymphoid organ and proliferates.
D. All of the above.
E. None of the above.
Adaptive immunity is all about generating
functional lymphocytes.
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node,
spleen and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Functional mature cells (entire body)
In the generation of diversity, why don’t
lymphocytes attack our own cells?
Because of tolerance: central and peripheral.
Central tolerance involves elimination of almost all
self-reactive lymphocytes at the site of production:
the primary lymphoid organs of bone marrow and thymus.
Peripheral tolerance involves suppressing immune responses
to antigens not eliminated in central tolerance.
How cells are gotten rid of in central tolerance.
By
apoptosis,
which is
noninflammatory.
Before B lymphocytes can migrate out of bone marrow,
all those cells bearing a BCR that reacts with a ‘self’
antigen bind to bone marrow stromal cells and die.
Apoptosis
T lymphocyte central tolerance.
T cells come in two flavors: CD4 and CD8 positive.
Both are generated randomly in the thymus by recognition
of a bit of antigen presented on a particular MHC molecule
in the context of either CD4 or CD8 binding.
Major histocompatibility complex antigens
(MHC)
1. MHC are cell surface molecules on APC that present
the bit of antigen to T lymphocytes.
2. There are two kinds of MHC: class I and class II.
3. Both molecules are fairly polymorphic ( different
choices in the population) and are heritable.
4. MHC class I has a one chain binding site while MHC
class II has two chains.
T cells must be activated by specific antigen presented by
MHC class II (to CD4 cells) and MHC class I (to CD8 cells)
MHC class I presents internal antigen and
MHC class II external antigen.
A chant for APC:
Internal proteins are processed and presented by MHC I
to CD8 positive T lymphocytes.
External proteins are processed and presented by MHC II
to CD4 positive T lymphocytes.
External pathogens are complexed by Ig molecules
produced by B lymphocytes.
Internal pathogens are killed (along with the host cell)
by CD8 positive CTL.
What do the CD4 positive T lymphocytes do?
The role of mature CD4 positive T lymphocytes
1. They provide ‘help’ in the form of cytokines in an antigenspecific manner to developing B cells that allow class-switching
and memory cell formation.
2. They provide ‘help’ in the form of cytokines in an antigen-specific
manner to developing CD8 positive T cells that greatly enhances
the response.
3. Mature CD4 positive T cells migrate to tissues and help clear
macrophages of infections (the so-called DTH response).
So what does CD4 and CD8 have to do with the process
of central tolerance in developing T cells?
This is called positive selection.
Negative selection occurs next and is similar to
the B cell process.
Cortex
Medula
3
4
3. The CD4/CD8 positive
thymocytes (double positive)
loose CD4 or CD8 to become
CD4 and CD8 T cells and
migrate to the medula.
4. In the medula, single
positive T cells can bind to
self peptide antigens
presented on MHC class I
or II on thymic dendritic
cells. If they do, they die.
Adaptive immunity is all about generating
functional lymphocytes.
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node
spleen and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Functional mature cells (entire body)
How does antigen get to lymphocytes?.
In three ways:
Through lymphatic ducts that lead to lymph nodes.
Through blood which goes to spleen.
Directly to lymphoid tissue through mucosal tissue (GALT)
MALT directly faces its antigen: an example is the gut.
The direct interface with outside is provided in the gut
by specialized M cells, which take up whole antigen and
feed it directly to macrophages, T and B cells inside it.
Secondary lymphoid tissues are where lymphocytes meets
antigen which comes from lymph ducts (and blood) that
connect to lymph nodes (or spleen).
The spleen is very much like the lymph node only it
does not have lymph node connection: only blood.
What form of antigen enters the secondary
lymphoid tissue?
Free antigen which
is necessary for
survival and proliferation
of B lymphocytes
Antigen inside a
dendritic cell,
a super APC, necessary
for T lymphocyte survival
and proliferation.
What are dendritic cells?
A kind of antigen presenting cell.
There are several
kinds of dendritic
cells, but only one
that brings antigen
into the lymph node.
Dendritic cells stationed beneath skin (a sentinal cell)
differentiate and migrate when encountering a
dangerous antigen.
To
regional
lymph
node
Activation
of specific
immune
response
Adaptive immunity is all about generating
functional lymphocytes.
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node
spleen and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Functional mature cells (entire body)
Now we have free antigen, antigen being processed
by dendritic cells and B and T lymphocytes
present in secondary lymphoid tissue, what
happens?
Free antigen binds to its BCR on B lymphocytes and stimulates
limited clonal proliferation and differentiation.
Dendritic cells present antigen to CD4 positive T lymphocytes
and stimulate clonal proliferation and differentiation.
Dendritic cells present antigen to CD8 positive T lymphocytes
and activate the cells for clonal expansion and differentiation.
The first and third stimulations occur much better with ‘T cell
help’ (from antigen-specific, mature CD4 positive helper cells).
The life cycle of a B lymphocyte.
Immune memory: a much larger and faster response
the second time around.
(IgM, IgG,
IgA, IgE)
(mostly
IgM)
These secondary effects are all due to CD4 T cell help.
Antigen driven clonal expansion and maturation without
T cell help.
APC
BCR
B lymphocyte
soluble IgM
clonal
expansion
maturation
Plasma cell
The B lymphocyte as an
APC
T helper cell
Antigen-specific BCR
Antigen
processing
into peptides
MHC
peptide
Help comes in the form of
cytokines,
soluble and cellassociated, produced by the
T helper cell.
Antigen-specific CD8 positive cells meet antigen
presented by a dendritic cell, receive help from
a T helper cell, clonally expand and mature into
a cytotoxic T lymphocyte (CTL).
MHC II
MHC I
activation of Thelper cells by antigen
presented by MHC
class II.
activation of CD8
positive T cell by
antigen presented
on MHC class I
clonal expansion
and maturation
Adaptive immunity is all about generating
functional lymphocytes.
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node
spleen and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Functional mature cells (entire body)
Output from secondary lymphoid tissue:
1. Plasma cells that produce Ig.
2. B memory cells with memory responses to specific
antigens, some already Ig class switched.
3. CD4 positive T helper effector cells that may or
may not travel to the periphery.
4. CD4 memory cells for every effector population.
5. CD8 positive (CTL) that travel to the periphery.
6. CD8 memory cells for every effector population.
A question for voting:
Where are most CD4 and CD8 T cells selected for
non-recognition of self antigens?
A. In the primary lymphoid organ (bone marrow).
B. In secondary lymphoid organs (lymph nodes
and spleen).
C. In the thymus at the end of their maturation process.
D. All of the above.
E. None of the above.
How do all these cells know where to go after
being activated?
They have receptors for or express chemokines, cell adhesion
molecules, integrins and selectins that guide them to where
they should go. We shall call them collectively addressins.
The role of addressins:
Spleen or lymph node
please.
Spleen or lymph node
Vascular endothelial cell
naïve B or T
cell
Addressins or addresses are combinations of lectins, integrins, cell
adhesion molecules (CAMs) and chemokines and chemokine receptors.
Addressins are the way immune cells find their way
through the process of maturation and find their
targeted infection.
mature T helper lymphocyte
Naïve T lymphocyte
Dendritic cell,
please
naïve B cell,
please
TCR
MHC with processed antigen
dendritic cell
BCR
naïve B cell
dendritic cell
naïve B lymphocyte
The vascular endothelium expresses addresses in response
to cytokines released by macrophages and mast cells
fighting the infection (innate response).
Effector B cells (plasma cells) have addressins that allow
them to accumulate in bone marrow, secondary lymphoid
organs or just beneath the epthelium.
They then start to secrete specific Ig.
lambda secretors = yellow
kappa = red.
medulary lymph nodes
IgA = red, IgG = green
bone marrow
A pre-CTL leaves a secondary lymphoid organ, enters
blood, extravasates into an inflamed tissue, migrates to
the site of infection then recognizes the cell to be
killed by the peptide in its MHC class I.
Death is by apoptosis, which
neatly packages everything
within a plasma membrane
which will be picked up by a
macrophage and disposed of.
Where antigen (vasicular stomatitis virus) specific
CTLs end up.
Mature CD4 T cells also migrate into blood, cross an
inflamed endothelium and are further activated by
interaction of their TCR with their antigen expressed
on MHC class II.
The result is activation of the macrophage by IFNg
released by the mature CD4 cell. This activation allows
the macrophage to kill internalized viruses, bacteria and
parasites.
Adaptive immunity is all about generating
functional lymphocytes.
Generation of cellular diversity (bone marrow and thymus)
Selection of cells specific to a given antigen (lymph node
spleen and mucosal tissue)
Clonal expansion of these cells (lymph node, spleen and
mucosal tissue)
Functional mature cells (entire body)