To initiate immune responses, antigens are captured from their site of entry and

concentrated in secondary (peripheral) lymphoid organs through which naive T cells

circulate constantly.

Microbes and other antigens most often enter the body through epithelium-lined surfaces,
which interface with the external environment. Microbes may also colonize any tissue, and
antigens may be produced in these tissues.
Because the total number of lymphocytes in the body is finite and the immune system
generates a large number of lymphocyte clones each with different specificity, there are very
few naive T and B cells specific for any one antigen, in the range of 1 in 10٨5 or 10٨6
lymphocytes.

This small number of naive T cells has to be able to locate and respond to the foreign antigen.
It is impossible for the few T cells specific for any antigen to constantly patrol all the possible
tissues where antigens may enter or be produced.
The mechanism that solves this problem is a specialized system for capturing an antigen from
its site of entry or production and bringing it to secondary lymphoid organs through which
naïve T cells circulate. The cells that capture antigens and display them to T lymphocytes are
called antigen-presenting cells (APCs).

Once helper and cytotoxic effector T cells are produced, they leave the lymphoid organs and
migrate to sites of infection and then recognize the same antigens that initiated the response
again presented by cells at these sites. Some helper T cells migrate toward follicles and then
recognize the same antigens presented by B cells. This second round of antigen presentation
activates the effector functions of the T cells so that they can eliminate the microbes or activate
the B cells.
T lymphocytes recognize and respond to cell-associated antigens and not to soluble,
cell-free antigens.

T cell antigen receptors have evolved to see antigens that are derived from proteins that are
inside cells and are displayed by cell surface molecules, which ensures that T cells recognize
cell-associated and not free antigens and interact with other cells.

This is in striking contrast to B lymphocytes, whose antigen receptors and secreted products,
antibodies, can recognize intact antigens on microbial and host cel surfaces, and soluble cell-
free antigens.

The task of displaying host cell–associated antigens for recognition by CD4+ and CD8+ T cells
is performed by specialized proteins called major histocompatibility complex (MHC)
molecules, which are expressed on the surfaces of host cells.
MHC molecules display antigens from different cellular compartments to different
classes of T cells, such that the correct type of T cell recognizes the type of microbe that T cell
is best at eliminating.

For instance, defense against microbes in the circulation has to be mediated by antibodies, and
the production of the most effective antibodies requires the participation of CD4+ helper T
cells.

But if the same microbe (e.g., a virus) infects a tissue cell, it becomes inaccessible to the
antibody, and its eradication may require that CD8+ cytotoxic T lymphocytes (CTLs) kill the
infected cells and eliminate the reservoir of infection.

MHC molecules play a critical role in displaying antigens that are internalized from outside
cells to CD4+ T lymphocytes and those that are produced inside cells to CD8+ T cells.
 APC

Naive T cells are best activated by antigens presented by DCs.

Many cell culture experiments showed that purified CD4+ T cells could not respond to protein
antigens, but they responded very well if non-T cells such as DCs or macrophages were added
to the cultures.

These results led to the concept that a critical step in the induction of a T cell response is the
presentation of the antigen to T lymphocytes by other cells, which were named antigen
presenting cells (APCs).

The first APCs identified were macrophages, and the responding T cells were CD4+ helper
cells. It soon became clear that several cell populations can function as APCs in different
situations.

By convention, APC is still the term used to refer to specialized cells that display antigens to
CD4+ T lymphocytes. As we will see later in this presentation, all nucleated cells can display
peptide antigens to CD8+ T lymphocytes, but they are not all called APCs.
 General properties of APC

• Different cell types function as APCs to activate naive T cells

or previously differentiated effector T cells (Fig. 6.2 and Table
6.2) .

DCs are the most effective APCs for activating naive T cells and therefore for initiating T cell
responses. Macrophages and B lymphocytes also function as APCs, but mostly for previously
activated CD4+ helper T cells rather than for naive T cells. DCs, macrophages, and B
lymphocytes express class II MHC molecules and are therefore capable of activating CD4+ T
lymphocytes. For this reason, these three cell types have been called professional APCs;
however, this term is sometimes used to refer only to DCs because of their unique role in naive
T cell activation.
 General properties of APC

• APCs display peptide-MHC complexes for recognition by T cells and also provide
additional stimuli that are required for the full responses of the T cells.

Antigen is the first signal, and these additional stimuli are sometimes called second signals.
They are more important for activation of naive T cells than for restimulation of previously
activated effector and memory cells. The membrane bound molecules of APCs that function
together with antigens to stimulate T cells are called costimulators. APCs also secrete
cytokines that play critical roles in the differentiation of naive T cells into effector cells.
 General properties of APC

The antigen-presenting function of APCs is enhanced by exposure to

microbial products.

This is one reason that the immune system responds better to microbes than to harmless,
nonmicrobial substances. DCs and macrophages express Toll-like receptors and other innate
immune microbial sensors and respond to microbes by increasing the expression of MHC
molecules and costimulators, by improving the efficiency of antigen presentation, and by
activating the APCs to produce cytokines, all of which help stimulate T cell responses. In
addition, DCs that are activated by microbes express chemokine receptors that facilitate their
migration to sites where naive T cells are present. The induction of optimal T cell responses to
purified protein antigens in the absence of infection requires that the antigens be administered
with substances called adjuvants. Adjuvants either are products of microbes, such as killed
mycobacteria (used experimentally), or substances that elicit innate immune responses, like
microbes do, and thus enhance the expression of costimulators and cytokines and also stimulate
the antigen-presenting functions of APCs. Adjuvants are routinely used in animal studies of
immune responses and in human vaccines.
 General properties of APC

APCs that present antigens to T cells also receive signals back from these
lymphocytes that enhance the antigen-presenting function of the APCs.

In particular, CD4+ T cells that are activated by antigen recognition and costimulation
express surface molecules, notably one called CD40 ligand (CD154), which binds to
CD40 on DCs and macrophages, and the T cells also secrete cytokines, such as
interferon-γ (IFN-γ), that bind to their receptors on these APCs. The combination of
CD40 signals and cytokines activates the APCs, resulting in increased ability to
process and present antigens, increased expression of costimulators, and secretion of
cytokines that activate the T cells. This bidirectional interaction between APCs
displaying the antigen and T lymphocytes that recognize the antigen functions as a
positive feedback loop that plays an important role in maximizing the immune
response.
 Role of DCs in Antigen capture and display

Microbes and protein antigens that enter through epithelia are

concentrated in lymph nodes, and blood-borne antigens are captured
mostly in the spleen (Fig. 6.3).

DCs are the cells that are best able to capture and transport antigens for presentation to naive T
cells. DCs function as tissue-resident sentinels that recognize microbes and trigger innate
immune reactions.
 Role of DCs in Antigen capture and display

DCs are divided into several subsets based on phenotypes and functions.

• Conventional (or classical) DCs (cDCs) are present in most epithelia that interface with the
external environment, such as the skin and the intestinal and respiratory tracts, and in tissues,
and are enriched in lymphoid organs. They are the DC subset that captures antigens and
transports them to secondary lymphoid organs and are thus involved in antigen presentation to
naive CD4+ and CD8+ T cells.

Conventional DCs are divided into two groups.

○ Type 1 cDCs (cDC1) are especially efficient at transferring ingested antigens from vesicles
into the cytosol. As we will discuss later, this is an essential step in the process of cross-
presentation, in which ingested antigens are presented on class I MHC molecules to
CD8+ T cells.

○ Type 2 cDCs (cDC2) are the major DC subset that presents captured antigens to CD4+ T
cells, and thus the subset that is most important for initiating responses of these T cells.
 Role of DCs in Antigen capture and display

DCs are divided into several subsets based on phenotypes and functions.

• Plasmacytoid DCs (pDC) are the body’s major source of type I IFN and are thus essential for
innate immune responses to viruses. pDCs also may capture antigens in the blood and
transport them to the spleen.

• Monocyte-derived DCs (moDC) can be induced to develop from monocytes under

inflammatory conditions. Their roles in immune responses are not clear.

• Langerhans cells of the epidermis were one of the earliest DCs identified. These cells are
related to tissue-resident macrophages and develop early in life from progenitors in the yolk sac
or fetal liver and seed the skin. Their function is probably similar to that of cDC2.
DCs that are resident in epithelia and tissues capture protein antigens.
Tissue-resident cDCs express numerous membrane receptors, such as C-type lectins, that bind
microbes. DCs use these receptors to capture and endocytose microbes or microbial proteins
and then process the ingested proteins into peptides capable of binding to MHC molecules. In
addition to receptor-mediated endocytosis and phagocytosis, DCs can ingest antigens by
pinocytosis, a process that does not involve specific recognition receptors but serves to
internalize whatever molecules might be in the fluid phase in the vicinity of the DCs.

Simultaneously with antigen capture, DCs are activated by microbial products to

mature into APCs that transport the captured antigens to draining lymph nodes (Fig.
6.4).
At the time that microbial antigens are being captured, microbial products (i.e., pathogen-
associated molecular patterns [PAMPs]), different from the protein antigens that T cells
recognize, are recognized by Tolllike receptors and other innate pattern recognition receptors in
the DCs and other cells, generating innate immune responses. The DCs are activated by these
signals and by cytokines, such as tumor necrosis factor (TNF), produced in response to the
microbes. The activated DCs (also called mature DCs) lose their adhesiveness for epithelia or
tissues and begin to express a chemokine receptor called CCR7 that is specific for two
chemokines, CCL19 and CCL21, that are produced in lymphatic vessels and in the T cell zones
of lymph nodes. These chemokines attract the DCs bearing microbial antigens into draining
lymphatics and ultimately into the T cell zones of the regional lymph nodes.
Naive T cells also express CCR7, and this is why they localize to the same regions of lymph
nodes where antigen-bearing DCs are concentrated, although their route into the lymph node is
via the blood. The colocalization of antigen-bearing activated DCs and naive T cells maximizes
the chance of T cells with receptors for the antigen finding that antigen.
Activation also converts the DCs from cells whose primary function is to capture
antigen into cells that are able to present antigens to naive T cells and to activate the
lymphocytes.

Activated DCs express high levels of MHC molecules with bound peptides and costimulators
required for T cell activation. Thus, by the timethese cells arrive in the lymph nodes, they have
developed into potent APCs with the ability to activate T lymphocytes. Naive T cells that
recirculate through lymph nodes encounter these APCs, and the T cells that are specific for the
displayed peptide-MHC complexes are activated. This is the initial step in the induction of T
cell responses to protein antigens. In the absence of infection or inflammation, conventional
DCs capture antigens in the tissues but are not activated to produce the high levels of cytokines
and costimulators that are required to induce effective immune responses. The function of these
DCs may be to present self antigens to self-reactive T cells and thereby cause inactivation or
death of the T cells or generate regulatory T cells. These mechanisms play a role in maintaining
self-tolerance and preventing autoimmunity.
 Antigen capture and transport

Several properties of conventional DCs make them the most efficient APCs for
initiating primary T cell responses.

• DCs are strategically located at the common sites of entry of microbes and foreign antigens
(in epithelia) and in tissues that may be colonized by microbes.
• DCs express receptors that enable them to capture and respond to microbes.
• In response to chemokines, activated DCs migrate from epithelia and tissues via lymphatics,
preferentially into the T cell zones of lymph nodes, and naive T lymphocytes also circulate
through the same regions of the lymph nodes.
• Mature DCs express high levels of peptide-MHC complexes, costimulators, and cytokines, all
of which are needed to activate naive T lymphocytes.
• Specialized DCs (cDC1) can transfer internalized proteins from phagosomes into the cytosol
and are thus efficient at cross-presenting antigens to CD8+ T cells. As we will see later, this
process is essential for initiating CD8+ T cell responses to many viruses and tumors.
 Introduction

• The major histocompatibility complex can be defined as a tightly linked cluster

of genes whose products play an important role in intercellular recognition and
in discrimination between self and non-self.
• The term ‘histo’ stands for tissue and ‘compatibility’ refers to ‘getting along or
agreeable’.
• They determine whether a grafted tissue will be accepted as self
‘histocompatible’ or rejected as non-self ‘histoincompatible’ by the host.
• The rejection of foreign tissue leads to an immune response to cell surface
molecules.
• The concept was first identified by Peter Gorer and George Snell.
 MHC molecules Characteristics
• The Major Histocompatibility complex is a genetic locus that encodes the glycoprotein
molecules (transplantation antigens) which are responsible for tissue rejection of grafts
between genetically unidentical individuals.
• It is also the molecule that binds the peptide antigens processed by Antigen-presenting Cells
and presents them to T-cells, hence they are responsible for antigen recognition by the T-cell
receptors.
• Unlike the B-cell receptors that directly interact with the antigens, the T-cell receptors have
an intertwined relationship with the MHC molecule, in that T-cell receptors can only receive
and bind processed antigens in form of peptides that are bound to the MHC molecule, and
therefore, T-cell receptors are specific for MHC molecules.
• In humans, the Major Histocompatibility complex is known as Human Leukocyte Antigen
(HLA). There are three common MHC molecules i.e class I, class II, and class III MHC
proteins.
• The genes of the MHC exhibit genetic variability; and the MHC has several genes for each
class hence it is polygenic.
• The MHC is also polymorphic, meaning a large number of alleles exist in the population for
each of the genes.
• Therefore, a large number of alleles exist in the population for each of the genes. Each
individual inherits a restricted set of alleles from his or her parent. Sets of MHC genes tend
to be inherited as a block or haplotype. There are relatively infrequent cross-over events at
this locus.
 MHC molecules Characteristics
• The structure of the MHC class I have two domains that are distant from each other, made
up of two parallel α helices on top of a platform that is created by a β-pleated sheet. The
general structure looks like a cleft whose sides are formed by the α helices and the floor is β-
sheet.
• Generally, the MHC molecules have a broad specificity for peptide antigens and many
different peptides can be presented by any given MHC allele binding a single peptide at a
time.
• The α helices forming the binding clefts are the site of the amino acid residues that are
polymorphic (varying allelic forms) in MHC proteins, meaning that different alleles can bind
and present different peptide antigens. For all these reasons, MHC polymorphism has a
major effect on antigen recognition.
• The function of T-cells on interaction with the MHC molecules reveals that the peptide
antigens associated with class I MHC molecules are recognized by CD8+ cytotoxic T-
lymphocytes (Tc cells) and MHC class-II associated with peptide antigens that are
recognized by CD4+ Helper T-cells (Th cells).
• The MHC in humans is known as human leukocyte antigens (HLA) complex.
MHC Expression

• Class III MHC genes encode various secreted proteins having immune
functions (e.g. complement proteins, TNF, etc.)
• Expression of MHC Molecule is increased by cytokines such as IFNα IFNβ
IFNγ and TNF.
• Transcription factors are major determinant of MHC molecule synthesis.
- CIITAA(Trans activator), RFX(Trans activator)
• Some viruses decrease MHC expression
- CMV,HBV, etc.
• Reduction MHC of may allow for immune system evasion.
Enhancement of class II MHC molecules expression by IFN
gamma
• Class I is found in almost all nucleated cells.
• Presents endogenous antigens
Features Of Class I and Class II molecules
Characteristic
S.N. MHC-I molecule MHC -II molecule
s

Have a restricted tissue distribution

and are chiefly found on
Present on almost all nucleated cells
1. Distribution macrophages, dendritic cells, B
including platelets.
cells, and other antigen-presenting
cells only.

MHC class I proteins are encoded by the MHC Class II proteins are encoded
2. Encoding genes
HLA-A, HLA-B, and HLA-C genes. by the genes of the HLA-D region.

Antigens presented by MHC class II

Nature of antigen Antigens presented by MHC class I
3. molecules are derived from
presented molecules are of endogenous origin.
extracellular proteins.
Class II molecules sample peptides
Cytosolic proteins; they sample peptides
outside the cell such as lysosomal
4. Antigen generated within the cell or those that may
proteins mostly internalized from
enter cytosol from phagosomes.
extracellular environment.

Enzymes involved in
5. Cytosolic proteasome Endosomal and lysosomal proteases
peptide generation
Features Of Class I and Class II molecules
Characteristic
S.N. MHC-I molecule MHC -II molecule
s

Peptide loading of
6. Endoplasmic reticulum Specialized vesicular compartment
MHC

Includes the ER transporter associated

Chaperones in ER; invariant chain
Peptide-loading with antigen processing (TAP1/2), tapasin,
7. in ER, Golgi and MHC Class II
complex the oxidoreductase ERp57, and the
compartment/Class II vesicle
chaperone protein calreticulin.
They are recognized by CD4 co-
Recognizing co- They are recognized by CD8 co-receptors
8. receptors through β1 and β2
receptor through the MHC Class I β2 subunit.
subunits.

9. Receptor T cell Present antigens to CD8+ T cells. Present antigens to CD4+ T cells.

MHC class I molecules consist of one

MHC class II molecules consist of
membrane-spanning α chain produced by
10. Structure two membrane-spanning chains, α
MHC genes, and one β chain produced by
and β both produced by MHC genes.
the β2-microglobulin gene.
Features Of Class I and Class II molecules
Characteristic
S.N. MHC-I molecule MHC -II molecule
s

11. Building amino acids Possess 8-10 amino acids Possess 13-18 amino acids.

Peptide binding α1 and β1 are peptide binding

12. α1 and α2 are peptide binding domains.
domains domains.

13. Invariant chain Has no invariant chain. Has an invariant chain.

Presence of abundant antigens target cell Presences of foreign antigens induce

14. Functional effect
for destruction. antibody production.

Serology and mixed lymphocyte

15. Detection Method Serology
reaction
 Class I MHC Pathway
Digestion of Proteins in Proteasomes
Cytosolic proteins are degraded in proteasomes to generates peptides that are able to
bind to class I MHC molecules.
The composition of proteasomes influences the peptides that areproduced.
Proteasomes are organelles whose basic cellular function has been adapted for a role
in antigen presentation. There are two types of proteasomes with specialized functions
in the immune system.
Immunoproteasomes are present in immune cells, such as DCs and other APCs. They
contain three unique catalytic subunits known as β1i, β2i, and β5i in the β ring. The
production of these subunits results in a change in the substrate specificity of the
proteasome such that the peptides produced usually contain carboxy-terminal
hydrophobic amino acids such as leucine, valine, isoleucine, and methionine or basic
residues such as lysine or arginine. These kinds of C termini are typical of peptides
that bind with high affinity to class I molecules. Thus, immunoproteasomes play an
important role in generating peptides from foreign proteins that stimulate CD8+ T
cells.
The second type of proteasome is called the thymoproteasome because it is present in
thymic epithelial cells. It contains a unique subunit called β5t, which confers upon it
the ability to produce peptides that bind weakly to class I MHC molecules. in the
thymus these peptides are derived from self proteins, and their low-affinity
recognition is important for the process of positive selection, which preserves
maturing T cells that strongly recognize foreign antigens.
 Class I MHC Pathway
Transport of Peptides From the Cytosol to the Endoplasmic Reticulum

Peptides generated by proteasomes in the cytosol are translocated By a specialized

transporter into the ER, where newly synthesized class I MHC molecules are available to
bind the peptides.
This delivery is mediated by a dimeric protein located in the ER membrane called transporter
associated with antigen processing (TAP), which is a member of the ABC transporter family
of proteins, many of which mediate ATP-dependent transport of low molecular- weight
compounds across cellular membranes. Although\ the TAP heterodimer has a broad range of
specificities, it optimally transports peptides ranging from 8 to 16 amino acids in length and
containing carboxyl termini that are basic or hydrophobic. As mentioned earlier, these are the
characteristics of the peptides that are generated in the proteasome and are able to bind to class
I MHC molecules.

Assembly of Peptide–Class I MHC Complexes in the Endoplasmic Reticulum

Peptides translocated into the ER bind to newly synthesized class I MHC molecules that are
associated with the TAP dimer through tapasin.
Peptides transported into the ER preferentially bind to class I but not class II MHC
molecules for two reasons.
First, newly synthesized class I MHC molecules are a􀄴 ached to the luminal aspect of the
peptide-loading complex, and they capture peptides rapidly as the peptides are transported into
the ER by TAP. Second, as discussed later, the peptide-binding clefts of newly synthesized
class II molecules in the ER are blocked by a protein called the invariant chain.
 Class I MHC Pathway

Surface Expression of Peptide–Class I MHC Complexes

Class I MHC molecules with bound peptides are structurally stable and are expressed on the
cell surface.
 Class II MHC Pathway

Ingestion of Protein Antigens Into Vesicles

Most class II MHC–associated peptides are derived from protein antigens that are
ingested into and digested in endosomes and lysosomes in APCs.
Different APCs can bind native protein antigens in several ways and with varying
efficiencies and specificities.

• DCs and macrophages express a variety of surface receptors, such as lectins, that
recognize structures shared by many microbes. These APCs use the receptors to bind
and internalize microbes efficiently.
• Macrophages also express receptors for the Fc portions of antibodies and receptors
for the complement protein C3b, which bind antigens that are opsonized by antibodies
or complement proteins and enhance antigen internalization.
• Another example of specific receptors on APCs is the surface Ig on B cells, which,
because of its high affinity for antigens, can effectively mediate the internalization of
proteins present at very low concentrations in the extracellular fluid
 Class II MHC Pathway
Ingestion of Protein Antigens Into Vesicles

Proteins other than those ingested from the extracellular milieu can also enter the
class II MHC pathway.

• Some protein molecules destined for secretion may end up in the same vesicles as class II MHC
molecules and may be processed instead of being secreted.
• Cytoplasmic and membrane proteins may be processed and displayed by class II MHC molecules. In
some cases, this may result from the enzymatic digestion of cytoplasmic contents, the process known as
autophagy. In this pathway, cytosolic proteins are trapped within membrane-bound vesicles called
autophagosomes, which fuse with lysosomes, and the cytoplasmic proteins are proteolytically
degraded. The peptides generated by this route may be delivered to the same vesicular compartment as
are peptides derived from ingested antigens. Autophagy is primarily a mechanism for degrading
cellular proteins and recycling their products as sources of nutrients during times of stress. It also
participates in the destruction of intracellular\ microbes, which are enclosed in vesicles and delivered
to lysosomes.
• Some peptides that associate with class II MHC molecules are derived from membrane proteins that
may be recycled into the same endocytic pathway as are extracellular proteins. Thus, even viruses,
which assemble in the
cytoplasm of infected cells, may produce proteins that are degraded into peptides that enter the class II
MHC pathway of antigen presentation. This may be a mechanism for the activation of viral antigen–
specific CD4+ helper T cells.
 Class II MHC Pathway

Proteolytic Digestion of Antigens in Acidic Vesicles

Internalized proteins are degraded enzymatically in late endosomes and lysosomes to
generate peptides that are able to bind to the peptide-binding clefts of class II MHC
molecules.
Biosynthesis and Transport of Class II MHC Molecules to Endosomes
Class II MHC molecules are synthesized in the ER and transported to endosomes with an
associated protein, the invariant chain (I i ), which occupies the peptide-binding clefts of the
newly synthesized class II MHC molecules (Fig. 6.17) .
Association of Processed Peptides With Class II MHC Molecules in Vesicles
Within the endosomal/lysosomal vesicles, the I i dissociates from class II MHC molecules by
the combined action of proteolytic enzymes and the HLA-DM molecule, and peptides derived
from protein antigens are then able to bind to the available peptidebinding clefts of the class
II MHC molecules (see Fig. 6.17) .
The HLA-DM molecule edits the repertoire of peptides being presented, favoring the display
of peptides that bind with high affinity to class II MHC molecules.
Expression of Peptide–Class II MHC Complexes on the Cell Surface
Class II MHC molecules are stabilized by the bound peptides, and the stable peptide–class II
complexes are delivered to the surface of the APC, where they are displayed for recognition
by CD4 + T cells.
Physiologic Significance of MHC–Associated Antigen Presentation

A) Nature of Effector T Cell Responses

The presentation of cytosolic versus vesicular proteins by the class I or
class II MHC pathway, respectively, determines which subset of T cells
will recognize antigens found in these two pools of proteins and is
intimately linked to the functions of the T cells.

• Endogenously synthesized antigens, such as viral and tumor proteins, are located in
the cytosol and are recognized by class I MHC–restricted CD8+ CTLs, which kill the
cells producing the intracellular antigens.
• Conversely, extracellular antigens usually end up in endosomal vesicles and activate
class II MHC–restricted CD4+ T cells because vesicular proteins are processed into
class II– binding peptides.
• CD4+ T cells function as helpers to stimulate B cells to produce antibodies and
activate macrophages to enhance their phagocytic functions, both mechanisms that
serve to eliminate extracellular antigens.
• Thus, antigens from microbes thatreside in different cellular locations selectively
elicit the T cell responses that are most effective at eliminating that type of microbe.
• This is especially important because the antigen receptors of CTLs and helper T cells
cannot distinguish between extracellular and intracellular microbes.
• By segregating peptides derived from these types of microbes, the MHC molecules
guide CD4+ and CD8+ subsets of T cells to respond to the microbes that each subset
can best combat.
B) Immunogenicity of Protein Antigens

MHC molecules determine the immunogenicity of protein antigens in two related ways.

• The epitopes of complex proteins that elicit the strongest T cell responses are the
peptides that are generated by proteolysis in APCs and bind most avidly to MHC
molecules.
If an individual is immunized with a protein antigen, in many instances the majority of the responding
T cells are specific for only one or a few linear amino acid sequences of the antigen. These are called the
immunodominant epitopes or determinants.

The proteases involved in antigen processing produce a variety of peptides From natural proteins, and
only some of these peptides possess the characteristics that enable them to bind to the MHC molecules
present in each individual (Fig. 6.18).

It is important to define the structural basis of immunodominance because this may permit the efficient
manipulation of the immune system with synthetic peptides.
An application of such knowledge is the design of vaccines. For example, a viral protein could be
analyzed for the presence of amino acid sequences that would form typical immunodominant epitopes
capable of binding to MHC molecules with high affinity. Such analyses can be done experimentally or
in silico.

Synthetic peptides containing these epitopes may be effective vaccines foreliciting T cell responses
against the viral peptides expressed in an infected cell. Similarly, peptides produced by mutated genes
in cancers are analyzed for their ability to bind to the class I MHC molecules in each patient with
cancer. The ones that bind are most likely to stimulate antitumor immunity in that patient.
B) Immunogenicity of Protein Antigens

MHC molecules determine the immunogenicity of protein antigens in two related

ways.
• The expression of particular class II MHC alleles in an individual determines the
ability of that individual to respond to particular antigens.

As discussed earlier, the Ir genes that control antibody responses are class II MHC
genes. They influence immune responsiveness because various class II MHC
molecules produced by different alleles differ in their ability to bind different
antigenic peptides and therefore to stimulate specific helper T cells.

The consequences of inheriting a given MHC allele depend on the nature of the
peptide antigens that can bind the MHC molecule encoded by that allele.

For example, if the antigen is a peptide from ragweed pollen, the individual who
expresses class II MHC molecules capable of binding the peptide would be genetically
prone to allergic reactions against pollen.

Conversely, some individuals do not respond to vaccines (such as hepatitis B virus

surface antigen vaccine), presumably because their HLA moleculescannot bind and
display the major peptides of the vaccine antigen.
Immunogenicity of Protein Antigens

FIGURE 6.18 Immunodominance of peptides. Protein antigens are processed to generate multiple peptides;
immunodominant peptides are the ones that bind best to the available class I and class II MHC molecules. The
illustration shows an extracellular antigen generating a class II–binding peptide, but this also applies to peptides of
cytosolic antigens that are presented by class I MHC molecules. APC, Antigen-presenting cell; MHC, major
histocompatibility complex.
 Cross presentation

In this pathway the ingested antigens are transported from the vesicles to the cytoplasm, from
where peptides enter the class I pathway.

This permissiveness for protein traffic from endosomal vesicles to the cytosol is most efficient
in a sunset of DCs.( at the same time the DCs can present the class II MHC –associated
peptides generated in the vesicles to CD4+ helper T cells, which are offen required to induce
full responses of CD8+ cells. )

This process is called cross-presentation or cross- priming, to indicate that one cell type( The
DC) can present antigens from another cell ( the virus –infected or tumor cells) and prime or
activate T cells specific for these antigens.
• Some HLA alleles occur at a much higher frequency in those suffering from certain diseases than in the general
population.
• The diseases associated with particular MHC alleles include autoimmune disorders, certain viral diseases,
disorders of the complement system, some neurologic disorders, and several different allergies.
• The association between HLA alleles and a given disease may be quantified by determining the frequency of
the HLA alleles expressed by individuals afflicted with the disease, then comparing these data with the
frequency of the same alleles in the general population. Such a comparison allows calculation of relative risk
(see Table 7-4).
• A relative risk value of 1 means that the HLA allele is expressed with the same frequency in the patient and
general populations, indicating that the allele confers no increased risk for the disease. A relative risk value
substantially above 1 indicates an association between the HLA allele and the disease.
• As Table 7-4 shows, individuals with the HLAB27 allele have a 90 times greater likelihood (relative risk of 90)
of developing the autoimmune disease ankylosing spondylitis, an inflammatory disease of vertebral joints
characterized by destruction of cartilage, than do individuals with a different HLA-B allele.
• The existence of an association between an MHC allele and a disease should not be interpreted to imply that the
expression of the allele has caused the disease—the relationship between MHC alleles and development of
disease is complex.
• In the case of ankylosing spondylitis, for example, it has been suggested that because of the close linkage of the
TNF- and TNF- genes with the HLA-B locus, these cytokines may be involved in the destruction of cartilage.
• When the associations between MHC alleles and disease are weak, reflected by low relative risk values, it is
likely that multiple genes influence susceptibility, of which only one is in the MHC. That these diseases are not
inherited by simple Mendelian segregation of MHC alleles can be seen in identical twins; both inherit the MHC
risk factor, but it is by no means certain that both will develop the disease.
• This finding suggests that multiple genetic and environmental factors have roles in the development of disease,
especially autoimmune diseases, with the MHC playing an important but not exclusive role.