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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

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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


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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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* 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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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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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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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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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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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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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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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


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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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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B Cells

A i P i B C ll d T C ll

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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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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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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


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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!


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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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T Cells


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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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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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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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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


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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.


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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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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


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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"


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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.


T Cells


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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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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.

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