Chapter 5 – Antigen Recognition by T Lymphocytes
I.
T-Cell Receptor (TCR) Diversity
a. T-cell receptor is a membrane bound glycoprotein that closely resembles a single
antigen-binding arm of an immunoglobulin molecule.
i. Composed of two different polypeptide chains and has one antigen binding site
ii. T cell receptors are ALWAYS membrane bound ; no secreted form
iii. During T cell development, gene rearrangement produces sequence variability
in the variable regions of the T cell receptor by the same mechanisms used by B
cells
iv. DIFFERENCE: After T cells are stimulated with antigen, there is NO further
change; no equivalent to somatic hypermutation or isotype switching.
1. This correlates with the fact that T cell receptors are ONLY used as
receptors to recognize antigen
b. T cell receptors consist of two different polypeptide chains: TCRα and TCRβ
i. Genes encoding these chains have germline organization similar to that of genes
encoding the immunoglobulin heavy and light chains – must be rearranged to
form a functional gene
ii. Each mature T cell expresses on functional α chain and one functional β chain
1. Each chain has a variable region and a constant region
2. The chains are folded into discreet protein domains, similar to those of
immunoglobulin chains
3. The antigen-recognition site of T cell receptors is formed from the Vα
and Vβ domains and is the most variable part of the molecule
4. Sequence variation in the chains is clustered into regions of
hypervariability, which corresponds to loops of the polypeptide chain at
the end of the domain farthest from the T cell membrane
a. Form binding site for antigen (CDRs)
b. The α and β chains each have three CDR loops: CDR1, CDR2, and
CDR3
iii. T cell receptors have a single antigen-binding site and antigen binding occurs in
the context of two opposing cell surfaces, where multiple copies of TCR bind to
multiple copies of the antigen:MHC complex on the opposing cell  multipoint
attachment
c. T-cell receptor diversity is generated by gene rearrangement
i. The human T-cell α chain locus is on chromosome 14 and the β chain locus is on
chromosome 7
ii. Organization of gene segments encoding these chains is essentially like that of
immunoglobulin gene segments; main difference is the simplicity of the T cell
receptor C regions: there is only one Cα gene and, although there are two Cβ
genes, no functional distinction between them is known
iii. TCR gene rearrangement occurs during T cell development in the thymus and
the mechanism is similar to that for the immunoglobulin genes
1. Genetic defects resulting from absence of RAG proteins: Severe
combined immunodeficiency disease (SCID) – functional B and T
lymphocytes are absent resulting in an inability to make an adaptive
immune response. Infants with SCID typically show infections with
opportunistic pathogens;
2. Missense mutation producing RAG proteins with partial enzymatic
activity: Omenn syndrome – genetic defect that results in 80% loss of
RAG activity; results in chronic inflammation
iv. After rearrangement, functional α and β chains consist of exons encoding the
leader peptide, the V region, the C regions and membrane-spanning region;
translation produces the newly synthesized chains, which then enter the
endoplasmic reticulum where they pair to form the α:β T cell receptor
d. RAG genes were key elements in origin of adaptive immunity
i. Components of a transposon could have evolved to become the RAG genes and
the recombination signal sequences of immunoglobulin and T-cell receptor
genes
ii. RAG genes lack introns that characterize eukaryotic genes – resemble the
transposase gene of a transposon (a type of genetic element that can make and
move copies of itself to a different chromosomal locations)
1. Transposon essential elements: transposase and terminal repeat
sequences – allow transposon to be excised and inserted into another
location
iii. The similarity of RAG recombinase and transposase has led to the suggestion
that the mechanism to rearrange immunoglobulin and T cell receptor genes
originated from the insertion of a transposon into some type of innate immune
receptor gene in a vertebrate ancestor
1. Inserted transposase genes evolved to encode the RAG proteins and the
terminal repeat sequences evolved to become recombination signal
sequences for the first rearranging gene segments
2. The transposase gene and the long terminal repeats of the transposon
became separated to become components of different genes, both
being specifically expressed in lymphocytes
e. Expression of the T cell receptor on the cell surface requires association with additional
proteins
i. T cell receptors are diverse and specific receptors for antigens.
ii. By themselves, however, heterodimers of α and β chains are unable to leave the
endoplasmic reticulum and be expressed on the T cell surface
1. Before leaving the E.R., and α:β heterodimer associates with four
invariant membrane proteins
f.
II.
a. Three of the proteins are encoded by closesly linked genes on
human chromosome 11 and are homologous to each other –
the CD3 Complex (CD3ϒ, CD3δ, and CD3ε)
b. The fourth protein, ζ, is encoded by a gene on human
chromosome 1
iii. Polypeptide composition of the T-cell receptor complex
1. The functional antigen receptor on the surface of T cells is composed of
eight polypeptides and is called the T cell receptor. The α and β chains
bind antigen and form the core T-cell receptor (TCR). They assoiate with
one copy of each of CD3ϒ and CD3δ and two copies each of CD3ε and
the ζ chain
a. These associated invariant polypeptides are necessary for the
transport of newly synthesized TCR to the cell surface and for
the transduction of signals to the cell’s interior after the TCR has
bound antigen.
b. The transmembrane domains of the α and β chains contain
positively charged amino acids, which form strong electrostatic
interactions with negatively charged amino acids in the
transmembrane regions of the CD3ϒ, δ, and ε genes
2. In people lacking functional CD3ϒ or CD3ε chains –TCR transport I I is
inefficient and their T cells have abnormally low numbers of receptors
that do not signal effectively  immunodeficiency
A distinct population of T cells expresses a second class of T cell receptor with ϒ and δ
chains
i. Second type of TCR – formed from a ϒ-chain and a δ-chain (1-5% of T cells in
circulation)
1. TCRϒ resembles the α chain and TCRδ resembles the β chain
ii. T cells express either α:β receptors OR ϒ:δ receptors – NEVER BOTH.
iii. Immune function of ϒ:δ T cells is less well-defined than that of α:β T cells, as are
the antigens to which these cells repond and the ligand that their receptors
engage
1. ϒ:δ T cells are NOT restricted to the recognition of peptide antigens
associated with MHC molecules
Antigen processing and presentation
a. A human T cell receptor can recognize antigen only in the form of a peptide bound to an
MHC molecule on the surface of another human cell
i. To be recognized by T cells, pathogen derived proteins must be degraded into
peptides (antigen processing); the peptides are then assembled in peptide:MHC
complexes for display on cell surfaces, where hey can be recognized by T cells
(antigen presentation)
b. The two classes of MHC molecule present antigen to CD8 and CD4 T cells, respectively
i. CD8 T cells are cytotoxic and their main function is to kill cells that have become
infected with a virus or some other intracellular pathogen
ii. CD4 T cells, or helper T cells, help other cells of the immune system to respond
to extracellular sources of infection.
1. Involved in stimulatin B cells to make antibodies; activate tissue
macrophages
2. HIV selectively infects CD4 T cells by exploiting the CD4 molecule as its
receptor.
a. On binding to CD4 on a T cell surface the virus gains entry into
the cell. As infection progresses, the number of CD4 T cells
gradually declines and eventually will reach a level at which the
adaptive immune response becomes fatally compromised
iii. MHC molecules are crucial to ensuring the appropriate class of T cells is
activated
1. MHC Class I molecules present antigens of intracellular origin to CD8 T
cells
2. MHC Class II molecules present antigens of extracellular origin to CD4 T
cells
c. The two classes of MHC molecule have similar three dimensional structures
i. An MHC Class I molecule is made of a transmembrane heavy chain, which is
noncovalently complexed with the small protein β2-microglobulin
1. Heavy chain has three extracellular domains (α1, α2, α3)
2. Peptide binding site is formed by folding of domains 1 and 2 (farthest
from the membrane), and is supported by domain 3 and the β2microglobulin
ii. An MHC Class II molecule consists of TWO transmembrane chains (α and β),
each of which contributes one domain to the peptide-binding site and one
immunoglobulin-like supporting domain
iii. The immunoglobulin like domains of MHC class I and II molecules are not just
for support of the peptide binding site – also provide specific binding sites for
CD4 and CD8 co-receptors
1. Sites on MHC molecule that interact with TCR and co-receptors are
separated – MHC can engage simultaneously
d. MHC molecules bind a variety of peptides
i. Promiscuous binding specificity – peptide binding site in an MHC molecule can
bind peptides of many different amino acid sequences
1. The peptide binding site is a deep groove on the surface of the MHC
molecule, within a single peptide is held tightly by noncovalent bonds
e. MHC class I and MHC class II molecules bind peptides in different intracellular
compartments
i. Peptide antigens that are presented by MHC molecules are generated inside
cells of the body by the breakdown of larger protein antigens. Proteins derived
from ‘intracellular’ and ‘extracellular’ antigens are present in intracellular
compartments
1. Intracellular – peptides are formed in the cytosol and delivered to the
endoplasmic reticulum; this is where MHC class I bind peptides
2. Extracellular – microorganisms and proteins are taken up by
phagocytosis and endocytosis into phagosomes and endocytic vesicles,
and they are degraded in the lysosomes and other vesicles of the
endocytic pathways; this is where MHC class II peptides bin peptides
f. Peptides generated in the cytosol are transported into the endoplasmic reticulum,
where they bind MHC class I molecules
i. Proteins in the cytosol are degraded by a large barrel-shaped protein complex
called the proteasome, which has several different protease activities
1. Consists of 28 polypeptide subunits
2. In the cells of healthy tissue, the proteasome is used to break down
proteins that are the innate immune system secrete IFN-ϒ, which causes
the tissue cells to change the proteasomes to favor the production of
peptides that bind to MHC class I molecules
3. Two proteasome subunits are replaced with alternative forms, and
another protein, the PA28 proteasome activator, binds to both ends of
the barrel – immunoproteasome
a. Specializes in making peptides having a hydrophobic or a basic
residue at the carboxy terminus, features that enable them to
bind MHC class I molecules
ii. Transport of peptides across the endoplasmic reticulum membrane is
accomplished by a protein, transporter associated with antigen processing
(TAP), embedded in the membrane
1. Is a heterodimer consisting of two structurally related polypeptide
chains, TAP-1 and TAP-2.
2. Peptide transport by TAP is dependent on the binding and hydrolysis of
ATP
3. The types of peptide that are preferentially transported by TAP are
similar to those binding MHC class I molecules
iii. MHC class I molecules bind antigenic peptide as part of a peptide-loading
complex
1. The correct folding and peptide loading of MHC class I molecules is
aided by proteins known as chaperones
a. Chaperones are proteins that assist in the correct folding and
subunit assembly of other proteins while keeping them out of
harm’s way until they are ready to enter cellular pathways and
carry out their function
b. When MHC class I heavy chains (α chains) first enter the
endoplasmic reticulum thy bind the membrane protein
calnexin, which retains the partly folded heavy chain in the
endoplasmic reticulum
i. Calnexin is a calcium dependent lectin , a carbohydrate
binding protein that retains multi-subunit glycoproteins,
including T cell receptors and immunoglobulins in the
endoplasmic reticulum until they have folded correctly
c. When the MHC class I heavy chain has bound β2macroglobulin, calnexin is released and the heterodimer is then
incorporated into the peptide-loading complex
i. This complex is composed of at least 6 proteins;
stabilizes the partly folded heterodimer of heavy chain
and β2-microglobulin and positions it to sample
peptides coming from the cytosol
1. This is achieved by disulfide bonded complex
ERp57 (oxidoreductase enzyme) and tapasin, a
bridging protein that binds to both the MHC
class I heavy chain and the TAP-1 subunit of the
peptide transporter
ii. Other components of the peptide-loading complex:
1. Protein disulfide isomerase (PDI) – stabilizs the
disulfide bond of the α2 domain of the class I
heavy chain
2. Calreticulin – resembles a soluble form of
calnexin and has a similar chaperone function
d. The heterodimer of the class I heavy chain and β2-microglobuin
will test various peptides for binding until it finds one that it is
compatible with, at this point the carboxy terminus of the
peptide witll fit well, but the peptide might be too long and
overhang the amino terminus
i. Endoplasmic reticulum aminopeptidase (ERAP) – will
remove amino acids from the amino-terminal end of
the peptide to improve its fit
e. On binding peptide, the completely assembled MHC class I
molecule is released from all chaperones and leaves the E.R. in a
membrane enclosed vesicle – travels to the plasma membrane
i. Cannot leave the E.R. until they have bound a peptide
1. Bare lymphocyte syndrome – TAP protein is
nonfunctional, no peptides enter the E.R.;
patients have <1% MHC class I molecules on
their cells and results in poor CD8 T cell
response to viruses
2. Protein degradation and peptide transport occur continuously
a. In the absence of infection, MHC class I molecules carry selfpeptides derived from normal human self-proteins, as do MHC
class II molecules
i. Typically does not provoke and immune response
because of mechanisms in T cell development to
eliminate or inactivate T cells that are reactive to selfpeptides
1. Sometimes this state of T cell tolerance to selfpeptides breaks down and leads to
autoimmunity
g. Peptides presented by MHC class II molecules are generated in acidified intracellular
vesicles
i. Proteins of extracellular bacteria, virus particles and soluble protein antigens are
processed by a different intracellular pathway from that of intracellular
antigens, and their peptide fragments end up bound to MHC class II molecules
ii. Phagocytic mechanisms produce intracellular vesicles known as endosomes or
phagosomes, in which the vesicular membrane is derived from the pasma
membrane and the lumen contains extracellular material
1. These phagosomes become part of an interconnected vesicle system
that carries materials to and from the cell surface
a. As vesicles travel inwards from the membrane, their interiors
become acidified by the action of proton pumps in the vesicle
membrane and they fuse with other vesicles, such as lysosomes,
that contain proteases and hydrolases that are active in acidic
conditions
b. Within the Phagolysosomes formed by this fusion, enzymes
degrade the vesicle contents to produce peptides from the
proteins and glycoproteins of the internalized pathogens
c. Peptides produced within the Phagolysosomes become bound
to MHC class II molecules within the vesicular system, and the
peptide:MHC class II complexes are carried to the cell surface by
outward going vesicles
*Certain pathogens (mycobacteria that cause leprosy and TB) exploit the vesicular system as a
protected site for intracellular growth and replication. Their proteins do not enter the cytosol and
therefore are not processed and presented to CD8 cytotoxic T cells by MHC class I molecules. They
protect themselves by lysosomal enzymes by preventing fusion of the phagosome with the lysosome
– also prevents presentation of mycobacterial antigens by MHC class II molecules
h. MHC class II molecules are prevented from binding peptides in the E.R. by the invariant
chain
i. Newly synthesized MHC class II α and β chains are translocated from ribosomes
and into the membranes of the E.R. where they associate with the invariant
chain (identical in ALL individuals)
1. One function of the invariant chain is to prevent the peptide-bonding
site formed by the association of an α and β chain from binding peptides
present in the E.R. – therefore these peptides are specifically targeted
by MHC class I
2. A second function of the invariant chain is to deliver MHC class II
molecules to endocytic vesicles, where they bind peptide
a. These vesicles, called MIIC (for MHC Class II Compartment),
contain proteases (e.g. cathepsin S) that selectively attack the
invariant chain; a series of cleavages leaves only a small
fragment of the invariant chain (called class II associated
invariant chain peptide, or CLIP) that covers up the MHC class
II peptide binding site
i. Removal of CLIP and binding of peptide is aided by the
interaction of the molecule with a glycoprotein called
HLA-DM in the vesicle membrane
1. HLA-DM resembles and MHC class II molecule
in structure, but does not bind peptides or
appear on cell surfaces
2. On binding to MHC class II, HLA-DM causes the
displacement of CLIP, allowing the MHC class II
molecule to sample peptides
3. Repeated rebinding to the MHC molecule
causes HLA-DM to displace weakly bound
peptides and make sure the MHC class II
molecule ends up with a strongly bound peptide
ii. When the MHC molecule has lost its invariant chain and
has a tightly bound peptide, it is carried to the cell
surface by outward going vesicles
i.
j.
The T cell receptor specifically recognizes both peptide and MHC molecule
i. When the T cell receptor binds to a peptide:MHC complex it makes contacts
with both the peptide and the surrounding surface of the MHC molecules –
thus, each complex forms a unique ligand for the T cell receptor
ii. In its overall organization, the T cell receptor antigen-binding site resembles
that of an antibody
1. Analysis of several peptide:MHC complexes has revealed similar
interactions for peptides bound to either MHC class I or class II
molecules
iii. MHC CLASS I –
1. The TCR binds to the peptide:MHC class I complex with the long groove
axis of its binding site oriented diagonally across the peptide-binding
groove of the MHC class I molecule
2. The CDR3 loops of the T cell receptor α and β chains form the central
part of the binding site and they grasp the side chain of one of the
amino acids in the middle of the peptide
3. CDR1 an CDR2 loops form the periphery of the binding site and contact
the α helices of the MHC molecule
4. The CDR3 loops that directly contact the peptide are the most variable
part of the TCR antigen recognition site
a. The α chain CDR3 includes the joint between the V and J
sequences
b. The β chain CDR3 includes the joints between V and D, the
whole of the D segment, and the joint between D and J
The two classes of MHC molecule are expressed differentially on cells
i. Virtually all cells of the body express MHC class I molecules constitutively, and
as all cell types are susceptible to infection by viruses, this enables
comprehensive surveillance by CD8 T cells
1. The erythrocyte is one cell type that lacks MHC class I, a property that
might facilitate its persistent infection by malaria parasites
ii. MHC class II molecules are constitutively expressed on only a few cell types,
which are cells of the immune system specialized for the uptake, processing,
and presentation of antigens from the extracellular environment
1. Distribution is consistent with MHC class II function, alerting CD4 T cells
to the presence of extracellular infections. To be effective, this function
need not be performed by every cell within tissue or organ, but requires
a sufficient number of cells equipped to guard the extracellular territory
a. Professional antigen presenting cells:
i. Dendritic cells – which are supremely specialized for
antigen presentation and the activation of T cells
ii. Macrophages – which take up antigens by
phagocytosis/endocytosis
iii. B cells – which efficiently internalize specific antigens
bound to their surface immunoglobulin
iii. During an immune response, cells can increase the synthesis and cell-surface
expression of MHC molecules beyond constitutive levels
1. This up-regulation, which enhances antigen presentation and T cell
activation, is induced by several cytokines produce by activated immune
system cells, particularly interferons
a. IFN-ϒ can induce the expression of MHC class II molecules on
some cell types that do not normally produce them
2. In this manner, presentation of antigen to CD4 T cells by MHC class II
molecules can be induced and increased in infected or inflamed tissues
k. Cross-presentation allows extracellular antigens to be presented by MHC class I
i. If a virus does not infect a professional antigen-presenting cell, it cannot be
presented as MHC class I-bound peptides derived from endogenously
synthesized viral proteins (e.g. hepatitis C)
1. In such situations, CD8 T cell response can still be generated via a third
pathway of antigen presentation
a. Involves endocytosis or phagocytosis of extracellular material
from virus-infected cells by professional antigen-presenting cells
and its delivery to the MHC class I pathway of antigen
presentation rather than to MHC class II (cross-presentation)
i. When an immune response is initiated by crosspresentation this is known as cross-priming of the
immune response
ii. Theory 1: Phagocytosis of dead, infected cells by the
professional antigen presenting cell allows complexes of
MHC class I and viral peptides to be transferred to the
membranes of intracellular vesicles inside the
professional antigen-presenting cell, with subsequent
transport to the cell surface where they can be engaged
by the T cell receptors of CD8 T cells
iii. Theory 2: viral components are delivered from
endocytic vesicles into the cytosol for degradation by
the proteasome and presentation by the usual MHC
class I pathway
III.
The Major Histocompatability Complex
a. MHC molecules and other proteins involved in antigen processing/presentation are
encoded in a cluster of closely linked genes – located on human chromosome 6
i. Called major histocompatibility complex because it was first recognized as the
site of genes that cause T cells to reject tissues transplanted from unrelated
donors to recipients
b. For some MHC class I and class II molecules, numerous genetic variants are present in
the human population
i. Each variant functions differently in the peptides it binds and the T cells it
triggers – helped survival against diverse and numerous pathogens
c. The diversity of MHC molecules in the human population is due to multigene families
and genetic polymorphism
i. The human MHC gene is called the human leukocyte antigen complex (HLA)
because the antibodies used to identify human MHC molecules react with the
white cells of the bloo, but not with the red cells
ii. MHC class I and II are encoded by conventionally stable genes that neither
rearrange or undergo any other developmental or somatic process of structural
change
1. Inherited diversity of MHC molecules has two components
a. Gene families – consist of multiple similar genes encoding the
MHC class I heavy chains, MHC class II α chains and MHC class II
β chains
b. Genetic polymorphism – the presence within the population of
multiple alternative forms of a gene
iii. The products of the different genes in a MHC class I or class II family are called
isotypes; the different forms of any given gene are called alleles; and their
encoded proteins are called allotypes
iv. The numerous alleles of certain MHC genes, and the many differences that
distinguish them, make these MHC genes stand out and are therefore
considered highly polymorphic.
v. MHC genes with no polymorphism are called monomorphic
vi. Genes having few alleles are described as oligomorphic
vii. In humans there are six MHC class I isotypes (HLA-A, HLA-B, HLA-C, HLA-E, HLAF, AND HLA-G) and five MHC class II isotypes (HLA-DM, HLA-DO, HLA-DP, HLADQ, and HLA-DR)
1. Of the class I isotypes, HLA-A, -B, and –C are highly polymorphic and
their function is to present antigen to CD8 T cells and to form ligand
receptors on NK cells; HLA-E and –G are oligomorphic and form ligands
for NK-cell receptors; HLA-F seems to be monomorphic and remains
intracellular, its function is unknown
2. Of the class II isotypes HLA-DP, -DQ, and –DR are highly polymorphic
and present peptide antigens directly to CD4 T cells; HLA-DM and –DO
are oligomorphic and have functions the regulate peptide-loading of
HLA-DP, -DQ, and –DO
d. The HLA class I and class II genes occupy different regions of the HLA complex
i. Class I region – at the end of the HLA complex farthest from the chromosome’s
centromere, contains 6 expressed HLA class I genes as well as several nonfunctional class I genes and gene fragments
ii. Class II region – at the opposite end of the complex; contains all the expressed
class II genes and several non-functional class II genes
iii. Class III region (central MHC) – separates the class I and class II regions; about 1
million base pairs; contains no class I or class II genes
iv. For each HLA class II isotype, the genes encoding the α and β genes are called A
and B respectively (e.g. HLA-DMA and HLA-DMB); when there is more than one
gene, including non-functional genes, a number in series is added (e.g. HLADQA1 and HLA-DQA2)
v. The particular combination of HLA alleles found on a given chromosome 6 is
known as the haplotype
1. Meiotic recombination occurs at a frequency of about 2%; in the
population, this mechanism reasserts the parental HLA genes into new
haplotypes, although in most families the parental HLA haplotypes are
inherited in tact
2. Individuals homozygous for the HLA complex are rare, but they are
usually healthy
e. Other proteins involved in antigen processing and presentation are encoded in the HLA
class II region
i. The class II region of the HLA is almost entirely dedicated to genes involved in
the processing of antigens and their presentation to T cells
1. Contains genes encoding the two polypeptides of TAP, the gene for
tapasin, and genes encoding two subunits of the proteasome called
LMP2 and LMP7
ii. Genes encoding proteins that work together in antigen processing and
presentation are regulated by cytokines IFN-α, -β, and –ϒ; stimulate cells to
increase their expression of HLA class I heavy chains, β2-microglobulin, TAP and
the LMP2 and LMP7 protease subunits
1. LMP2 and LMP7 are not constitutive components of the proteasome in
healthy cells, but are components of the immunoproteasome made
specifically in response to interferon
2. Expression of the HLA-DM, -DP, -DQ, -DR and invariant chain gene is
coordinated by IFN-ϒ
a. These genes are turned on by a transcriptional activator, MHC
class II transactivator (CIITA), which is itself induced by IFN-ϒ
iii. The majority of genes in the class I region are not involved in the immune
system; neither do the class I genes form as a compact cluster as the class II
genes
iv. MHC class II molecules are dedicated components of adaptive immunity that
serve only to present antigen to T cells, whereas MHC class I molecules
encompass a broader range of function (uptake of IgG in the gut, regulation of
iron metabolism, and regulation of NK-cell function in the innate immune
response)
f.
MHC polymorphism affects the binding and presentation of peptide antigen to T cells
i. In the HLA class I molecule, allotype variability if clustered in specific sites within
the α1 and α2 domains. These sites line the peptide-binding groove, lying either
in the floor of the groove, where they influence peptide binding, or in the α
helices that form the walls, which are also involved in binding TCRs
ii. In the HLA class II molecule, variability is only found in the β1 domain because
the α chain is monomorphic
iii. Anchor residues – anchor the peptide to the MHC molecule
1. The combination of anchor residues to a particular MHC isoform is
called its peptide-binding motif
a. For MHC class I, which bind mostly nonamer peptides, positions
2 and 9 are the usual anchor residue.
b. For MHC class II the anchor residues are less clearly defined
because of the heterogeneity in length of the bound peptides
2. In the complex of peptide bound to an MHC molecule, the anchor
residues are buried and inaccessible to a TCR. In contrast, the peptides
other positions are available for contact – these form part of the planar
surface that interacts with the TCR and include variable residues on the
upper surfaces of the α helices of the MHC molecule
a. MHC restriction – basic principle of T-cell biology in that
antigen-specific T cell response is restricted by MHC type
i. As a result, a T cell responding to a peptide on one MHC
allotype will not respond to another peptide bound by
that same allotype or to the same peptide bound to
another MHC allotype
g. MHC diversity results from selection by infectious disease
i. For an individual the advantage of having multiple MHC class I and class II genes
is that they contribute different peptide-binding specificities, allowing a greater
number of pathogen-derived peptides to be presented during any infection
(improves immune response strength)
1. Same argument applies to polymorphism at any given MHC locus
ii. Balancing selection – type of evolutionary selection that acts to maintain a
variety of phenotypes (such as different variants of MHC molecules) in a
population
iii. Directional selection – type of natural selection that replaces older alleles with
newer variants (for example in the MHC); its characteristic outcome is change
iv. Interallelic conversion or segmental change – mechanism of genetic
recombination between two alleles of a locus in which a segment of one allele is
replaced with the homologous segment from another. This is used to generate
new HLA class I and class II alleles. Segmental change can also include exchange
of a homologous segment between two different genes in a gene family (e.g.
between HLA-C and HLA-B)
h. MHC polymorphism triggers T cell reactions that can reject transplanted organs
i. Self-MHC are autologous ; all other MHC isoforms are allogeneic
ii. In every person’s circulation there are T cells that can respond to complexes of
peptide and allogeneic MHC class I and II molecules that are present in the
healthy cells of other individuals
1. T cells with this property are alloreactive ; those reactive against any
given allogeneic cell constitute between 1 and 10% of circulating T cells
iii. When allogeneic kidneys are transplanted into patients, a major danger is that
the kidney will be rejected by the patient’s immune system
1. Alloreaction – a potent T cell response that attacks the graft
2. To reduce the probability, donors may be selected who have identical or
similar HLA alleles to the patient’s ; Immunossuppressive drugs are also
used to preempt alloreaction and to treat rejection when it occurs
3. A natural situation in which alloreactions occur is pregnancy – the
mothers immune system can be stimulated by the HLA molecules of the
fetus that derive from the father but are not expressed on the mother’s
cells
a. Leads to alloantibodies – any antibody raised in one member of
a species against an allotypic protein from another member of
the same species.
b. Are of no harm to fetus-however can prove problematic if the
mother should need a kidney transplant in the future
i. If pre-existing alloantibodies react with allogeneic MHC
class I of the transplanted kidney cells, they cause a
type of graft rejection that is almost impossible to treat
ii. To avoid – pretest patient’s sera for reactivity with
potential donor’s leukocytes and transplantation is only
undertaken when the reaction is acceptably low