sel b&t.ppt
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Antigen Presentation
Antigens are macromoleculesthat elicit animmune response in the body. Antigens can be Proteins
Polysaccharides Conjugates of lipids with
proteins (lipoproteins) and
polysaccharides (glycolipids).
Most of this page will describe how proteinantigens are presented to the immune system.
The presentation of lipid and polysaccharideantigens will be mentioned at the end
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It will be helpful to distinguish between
* Antigens that enter the body from the environment; these wouldinclude
inhaled macromolecules (e.g., proteins on cat hairs that can trigger
an attack of Asthmain susceptible people)
ingested macromolecules (e.g., shellfish proteins that trigger an
Allergic responsein susceptible people)molecules that are introduced beneath the skin (e.g., on a splinter or
in an injected vaccine)
* Antigens that are generated within the cells of the body; these would
includeproteins encoded by the genes of viruses that have infected a cell
aberrant proteins that are encoded by mutant genes; such as mutated
genes in cancer cells
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Antigen Presentation
Antigen
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In all cases, however, the initial immune responseto any antigen
absolutely requires that the antigen be recognized by a T
lymphocyte(T cell").The truth of this rule is clearly demonstrated
in AIDS: the infections (viral or fungal or bacterial) that so often
claim the life of AIDS patients do so when the patient has lost
virtually all of his or herCD4+ T cells.
The two categories of antigens are processed and presented to T cellsby quite different mechanisms.
* First Group: Exogenous antigens
Exogenous antigens (inhaled, ingested, or injected) are taken up by
antigen-presenting cells(APCs). These include:
phagocytic cellslike dendritic cellsand macrophages;
B lymphocytes(B cells"); which are responsible for
producing antibodiesagainst the antigen
Antigen Presentation
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Antigen Presentation
Antigen-presenting cells :Engulf the antigen by endocytosis.
The endosome fuses with a lysosome where the antigen is
Degraded into fragments (e.g. short peptides).
These antigenic peptides are then displayed at the surface of the
cell nestled within a
Class II Histocompability Molecule.
Here they may be recognized by CD4+T cells.
(Dendritic cells can also present intactantigen directly to B cells. In
this case, the engulfed antigen is not degraded in lysosomes but isreturned to the cell surface for presentation to B cells bearing B CRs
of the appropriate specificity.)
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Antigen Presentation
* Second Group: Endogenous antigens
Antigens that are generated within a cell (e.g., viral proteins in any
infected cell) are
degraded into fragments (e.g., peptides) within the cell anddisplayed at the surface of the cell nestled
within a
class I histocompatibility molecule.
Here they may be recognized by CD8+T cells.
Most CD8+T cells are cytotoxic.
They have the machinery to destroy the infected cell (often before
it is able to release a fresh crop of viruses to spread the infection).
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Antigen Presentation
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Antigen Presentation
Transferring viral antigens to Antigen-Presenting Cells (APCs)
"Professional" antigen-presenting cells(APCs) like dendritic cells
can use the class I as well as the class II pathways of antigen
presentation.This is fortunate because:
Most viruses infect cells other than APCs.
While viral antigens displayed on the surface of infected cells can
serve as targetsfor cytotoxic T cells(CTLs),The lack of any costimulatory moleculeson the cell surface makes
them poor stimulantsfor the development of clones of CTLs in
the first place
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Antigen Presentation
However, at least two mechanisms exist for transferring viral
antigens from any infected cell to a professional APC.1. When an infected cell dies, it can be engulfedby a professional
APC and the viral antigens within it can enter the class I pathway.
The dead cell is engulfed by phagocytosis as described above.
The endosome that forms fuses with a lysosome and
degradation of the dead cell begins.
Viral antigens pass into the cytosol and are degraded in
proteasomes.
The viral peptides formed are then are picked up by TAP
and, as described above, Inserted into class I MHC molecules and
Displayed at the cell surfacealong with the costimulatory
molecules needed to start a vigorous clonal expansion of
CD8
+
cytotoxic T cells.
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Antigen Presentation
2. Cells infected with viruses can also transfer viral peptides directly
from their cytosol to an adjacent cell like
a professional APC able to present the peptidewith the
needed costimulatory moleculesto CTLs;
or simply a cell of the same type that can then present it in aclass I molecule and be killed by a CTL before the infection
can spread to it. This mechanism provides a way of walling
off the infection.
In both cases, the transfer occurs through gap junctionslinking the adjacent cells
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Antigen Presentation
B Cells and T Cells
Lymphocytes are one of the five kinds of white blood cellsor
leukocytes), circulating in the blood.
Although mature lymphocytes all look pretty much alike, they are
extraordinarily diverse in their functions. The most abundant
lymphocytes are:
B lymphocytes (often simply called B cells) and
T lymphocytes (likewise called T cells).
B cells are not only produced in the bone marrowbut also mature
there.However, the precursors of T cells leave the bone marrow and
mature in the thymus(which accounts for their designation).
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Each B cell and T cell is specificfor aparticular antigen. What this means is thateach is able to bind toa particular
molecular structure.The specificity of binding resides in areceptorfor antigen:
the B cell receptor (BCR) for antigen and
the T cell receptor (TCR) respectively.
Antigen Presentation B Cells and T Cells
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Antigen Presentation B Cells and T Cells
Both BCRs and TCRs sharethese properties:
They are integral membrane proteins.
They are present in thousands of identical
copies exposed at the cell surface.They are made before the cell ever
encounters an antigen.
They are encoded by genes assembled by the
recombination of segments of DNA.
How antigen receptor diversity is generated.
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Antigen Presentation B Cells and T Cells
They have a unique binding site. This site binds to a portion of the antigen called an antigenic
determinantor epitope.
The binding, like that between an enzymeand its substrate
depends on complementarity of the surface of the receptor and
the surface of the epitope.
The binding occurs by non-covalent forces(again, like an enzyme
binding to its substrate).
Successful binding of the antigen receptor to the epitope, if
accompanied by additional signals, results in:- stimulation of the cell to leave G
0and enter the cell cycle.
- Repeated mitosis leads to the development of a cloneof
cells bearing the same antigen receptor; that is, a clone of
cells of the identical specificity
C C
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Antigen Presentation B Cells and T Cells
BCRs and TCRs differin:
their structure;
the genes that encode them;
the type of epitope to which they bind.
B C ll d T C ll
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B Cells
Antigen Presentation B Cells and T Cells
BCRs bind soluble antigens (like diphtheria
toxoid, the protein introduced into your body
in the DTP vaccine). The bound antigen molecules are engulfed
into the B cell by receptor-mediated
endocytosis. The antigen is digested into fragments
B C ll d T C ll
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Antigen Presentation B Cells and T Cells
B Cells
Which are then displayed at the cell surface nestled inside a class II
histocompatibility molecule.
Helper T cells specific for this structure (i.e., with complementary TCRs)
bind the B cell and
Secrete lymphokinesthat:
- Stimulate the B cell to enter the cell cycle and develop, by repeated
mitosis, into a cloneof cells with identical BCRs;
- Switch from synthesizing their BCRs as integral membrane
proteins to a soluble version;
- Differentiate into plasma cellsthat secrete these soluble
BCRs, which we now call antibodies
A i P i B C ll d T C ll
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Antigen Presentation B Cells and T Cells
B Cells
A i P i B C ll d T C ll
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Antigen Presentation B Cells and T Cells
T Cells
The surface of each T cell also displays thousands of identical T cell
receptors(TCRs).
There are two types of T cells that differ in their TCR:
Alpha chain with a beta chain. Each chain has a variable (V)region and a constant (C) region. The V regions each contain 3
hypervariable regionsthat make up the antigen-binding site.
Gamma/delta() T cells. Their TCR is also a heterodimer of
a gamma chain paired with a delta chain.
The discussion that follows now concerns alpha/beta T cells.
Gamma/delta T cells, which are less well understood, are discussed
at the end
A ti P t ti B C ll d T C ll
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Antigen Presentation B Cells and T Cells
T Cells
The TCR (of alpha/beta T cells) binds
a bimolecular complex displayed at
the surface of some other cellcalled
an antigen-presenting cell(APC).This complex consists of:
A fragment of an antigen lying
within the groove of a
Histocompatibility molecule
The complex has been
compared to a "hot
dog in a bun
A ti P t ti B Cells and T Cells
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Antigen Presentation B Cells and T Cells
T Cells
Most of the T cells in the body belong to one of
two subsets. These are distinguished by the
presence on their surface of one or the otheroftwo glycoproteinsdesignated:
CD4
CD8
A ti P t ti B Cells and T Cells
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Antigen Presentation B Cells and T Cells
T Cells
Which of these molecules is present determines what types of cellsthe T cell can bind to.
CD8+T cells bind epitopes that are part of class I
histocompatibility molecules. Almost all the cells of
the body express class I molecules. CD4+T cells bind epitopes that are part of class II
histocompatibility molecules. Only specialized
antigen-presenting cells express class II molecules.
These include:
dendritic cells
phagocytic cells like macrophagesand
B cells!
A ti P t ti B Cells and T Cells
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Antigen Presentation B Cells and T Cells
T Cells
CD8+T cells
The best understood CD8+T cells are cytotoxic T
lymphocytes(CTLs). They secrete molecules that destroy
the cell to which they have bound.
This is a very useful function if the target cell is infected
with a virus because the cell is usually destroyed before it
can release a fresh crop of viruses able to infect other cells
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Antigen Presentation B Cells and T Cells
T Cells
Antigen Presentation B Cells and T Cells
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Antigen Presentation B Cells and T Cells
T Cells
An example will show the beauty and biological efficiency ofthis mechanism.
Every time you get a virus infection, say influenza (flu), the
virus invades certain cells of your body (in this case cells of the
respiratory passages). Once inside, the virus subverts themetabolism of the cell to make more virus. This involves
synthesizing a number of different macromolecules encoded by
the viral genome.
In due course, these are assembled into a fresh crop of virus
particles that leave the cell (often killing it in the process) and
spread to new target cells.
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Antigen Presentation B Cells and T Cells
T Cells
Except while in transit from their old homes to their new, theviruses work inside of your cells safe from any antibodies that
might be present in blood, lymph, and secretions.
But early in the process, infected cells display fragments of
the viral proteins in their surface class I molecules. CTLs
specific for that antigen will be able to bind to the infected cell
and often will be able to destroy it before it can release a fresh
crop of viruses.
In general, the role of the CD8+T cells is to monitor all the
cells of the body, ready to destroy any that express foreignantigen fragments in their class I molecules
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Antigen Presentation B Cells and T Cells
T Cells
CD4+T cells
CD4+T cells bind an epitope consisting of an antigen fragment
lying in the groove of a class II histocompatibility molecule.
CD4+T cells are essential for both the cell-mediatedand
antibody-mediated branches of the immune system:
a. Cell-mediated immunity
These CD4+cells bind to antigen presented by antigen-
presenting cells (APCs) like phagocytic macrophagesand
dendritic cells. The T cells then release lymphokinesthatattract other cells to the area. The result is inflammation: the
accumulation of cells and molecules that attempt to wall off
and destroy the antigenic material (an abscess is one example,
the rash following exposure to poison ivy is another).
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Antigen Presentation B Cells and T Cells
T Cells
b. Antibody-mediated immunity
These CD4+cells, called helper T cells, bind to antigen
presented by B cells (as shown above). The result is the
development of clonesof plasma cellssecreting antibodies
against the antigenic material
CD4+T cells
Antigen Presentation B Cells and T Cells
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Antigen Presentation B Cells and T Cells
T Cells
AIDS patients lose their CD4+T cells
AIDS provides a vivid and tragic illustration of the
importance of CD4+T cells in immunity. The human
immunodeficiency virus (HIV) binds to CD4 moleculesand thus is able to invade and infect CD4+T cells. As the
disease progresses, the number of CD4+T cells declines
below its normal level of about 1000 per microliter (l).
(A partial explanation for this may be the unceasing efforts
of the patient's CD8+T cells to destroy the infected CD4+
cells. However, it turns out that only a small fraction of the
patients CD4+T cells are infected at any given time.
Antigen Presentation B Cells and T Cells
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Antigen Presentation B Cells and T Cells
T Cells
When the number of CD4+T cells drops below 400 per
microliter, the ability of the patient to mount an
immune response declines dangerously. Not only does
the patient become hypersusceptible to pathogens that
give all of us grief but also to microorganisms,
especially viruses and fungi, that normally inhabit our
tissues without harming us. Eventually the patient dies
of these opportunistic infections
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Antigen Presentation B Cells and T Cells
T Cells
Building the T-cell Repertoire
T cells have receptors (TCRs) that bind to antigen fragments
nestled in MHC molecules. But,
All cells express class I MHCmolecules containing
fragments derived from self proteins; Many cells express class II MHCmolecules that also
contain self peptides.
This presents a risk to the animal of the T cells recognizing these
self-peptide/self-MHC complexes and mounting an autoimmuneattackagainst them. Fortunately, this is usually avoided by a
process of selection that goes on in the thymus (where all T cells
develop
Antigen Presentation B Cells and T Cells
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Antigen Presentation B Cells and T Cells
T Cells
The process works like this:
The precursorsof T cellslike all blood cellsare
formed in thebone marrow.
These cells then migrate to the cortexof the thymus. At
this time they have neither a complete TCR nor eitherCD4 or CD8 (thus are called "double-negative" or DNcells).
In the cortex of the thymus, they
- Begin to form a TCR;
- Synthesize both CD4 and CD8 (so now they are
"double-positive" or DPcells).
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Antigen Presentation Ce s d Ce s
T Cells
- The cortical cells of the thymus express a wide
variety of small molecules, usually a peptide of 68amino acids derived from body proteins; that is,
"self" proteins such as
proteins within the cytosol
serum proteins; i.e., proteins circulating in theblood and lymph
nestled in a histocompatibility molecule (encoded by
the MHC).
- Most of the cells (~97%) will produce a TCR that
does not bind to any of the peptide-MHC moleculespresent on the surface of the cortical cells. Unless
they can try again with a new TCR, these cells die by
"neglect"
Antigen Presentation B Cells and T Cells
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Antigen Presentation
T Cells
- Those remaining cells whose TCR
has bound a peptide antigen presented in class IIMHC molecule stop expressing CD8 and become
CD4+T cells. It is these cells that will go on to
become
Th1cells in cell-mediated immune responses;
Th1 helper cells for cytotoxic T lymphocytes(CTLs);
Th2helper cells for B cells
has bound a peptide antigen presented in class I
MHC molecule stop expressing CD4 and becomeCD8+T cells.
- Both sets of cells are said to have undergone positive
selection
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After positive selection, these cells migrate to the medullaof thethymus.
There those cells whose TCR binds very strongly to complexes of
self-peptide and self-MHC are destroyed
This process of negative selectionis important as it eliminates cells
that might otherwise mount an autoimmune attack. It is one of theways in which toleranceto self antigens is achieved.
The cells whose TCRs bind antigen at an affinity below the
threshold that triggers apoptosis are free to leave the thymus and
migrate throughout the immune system(lymph nodes, spleen, etc.)It is this population which we depend on to mount immune
responses against foreign antigens. A TCR that binds self-
peptide/self-MHC with low affinity may well bind a foreign-peptide
in self MHC with high affinity.
Antigen Presentation
T Cells
Antigen Presentation B Cells and T Cells
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Antigen Presentation
T Cells
Gamma/Delta () T Cells
Gamma/delta T cells differ from their alpha/beta cousins in several ways:
Their TCR is encoded by different gene segments.Their TCR binds to antigens that can be
intact proteins (just as antibodies do) as well as a variety of other types
of organic molecules (often containing phosphorus atoms).
not"presented" within class I or class II histocompatibility molecules;
not presented by "professional" antigen-presenting cells (APCs) likedendritic cells.
Most of these T cells have neither CD8 nor CD4 on their surface. This makes
sense because they have no need to recognize class I and class II
histocompatibility molecules.
Gamma/Delta T cells, like alpha/beta T cells, develop in the thymus.
However, they migrate from there into body tissues, especially epithelia (e.g.,
intestine, skin, lining of the vagina), and don't recirculate between blood and
lymph nodes (they represent no more than 5% of the T cells in the blood and
are even rarer in lymph nodes). They encounter antigens on the surface of the
epithelial cells that surround them rather than relying on the APCs found in
lymph nodes
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Antigen Presentation
T Cells
What is the Function of T cells?
That is still something of a mystery.
Situated as they are at the interfaces between the external and internal
worlds, they may represent a first line of defense against invading
pathogens. Their response does seem to be quicker than that of T
cells.Curiously, many of the antigens to which T cells respond are
found not only on certain types of invaders (e.g., Mycobacterium
tuberculosis, the agent of tuberculosis) but also in host cells that are
under attack by pathogens.
Knockout mice that cannot make T cells are slower to heal injuries
to their skin. They are also much more susceptible to skin cancers
than normal mice. Perhaps, immune surveillanceis one of the
functions of T cells.