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The Major Histocompatibility
Complex
MHC
• The immune system relies on many regulatory mechanisms that govern its ability to respond to infectious agents and neoplastic tissues, but no single scheme is as much a cellular and molecular microcosm of complex biologic systems as that controlled by the Major Histocompatibility Complex (Mhc).
Introduction• The task of displaying cell-associated antigens
for recognition by T cells is performed by specialized proteins that are encoded by genes in a locus called the MHC
• It was discovered as an extended locus containing highly polymorphic genes that determined the outcome of tissue transplants exchanged between individuals
• The physiologic function of MHC molecules is the presentation of peptides to T cells
• In fact, MHC molecules are integral components of the
ligands that most T cells recognize
• The antigen receptor of T cells are actually specific for
complexes of foreign peptide antigens and self MHC
molecules
• A cluster of closely linked genetic loci comprise the
MHC encoding molecules important in immune
functions
• Every vertebrate species examined so far has MHC; in
humans it is called The human leukocyte antigen
(HLA)
The MHC gene region
MHC class I and class II are polygenic
(several loci encoding products with essentially the same function)
a chain
a chain a chain
Class II
b2 microglobulin is not encoded in
MHC
Class I
Identification of Human MHC
• Multiparous women, actively immunized
volunteers, recipients of blood transfusion, and
transplanted patients were sources of anti-HLA
antibodies
• HLA antigens were identified in workshops with
exchange of antisera between researchers
• Initially HLA antigens were identified by
serology and the mixed lymphocyte reaction
(MLR)
Structural Characteristics of MHC
molecules• Each MHC molecule consists of an extracellular
peptide binding cleft, a groove, followed by a pair of Ig- like domain and is anchored to the cell by transmembrane and cytoplasmic domains
• Class I molecules are composed of one polypeptide chain encoded in the MHC and a second, non MHC-encoded chain ( β2 microglobulin), whereas class II molecules are made up of two MHC-encoded polypeptide chains
• The polymorphic amino acid residues of MHC molecules are located in and adjacent to the peptide-binding cleft (a1 and a2 in class I and a1 and β1 in class II. Variation is most in the β chain)
Structure of MHC molecules
• The display of MHC-peptide complexes is
scrutinized by TCRs on T cells and is crucial for
the initiation of adaptive immune responses
• Recently, several genes have been found within
the MHC whose products are important to the
function of MHC class I and II molecules
involved in antigen processing and presentation
• Class III molecules include some of the
elements of serum complement system
Genomic Organization of the MHC
• MHC is located on the short arm of chromosome 6, β2 microglobulin on chromosome 15
• It occupies a large segment of DNA, extending about 3500 kb ( about 4 cetrimorgans) meaning that crossovers within the MHC occur with a frequency of about 4% at each meiosis
• Within the MHC locus are genes that encode several proteins that play critical roles in antigen processing
• One of these proteins, called the transporter associated with antigen processing (TAP), is a heterodimer that transports peptides from the cytosol into the endoplasmic reticulum, where the peptide can associate with the newly synthesized class I molecules
• Other genes in the cluster encode subunits of a cytosolic protease complex, called the proteasome, that degrades cytosolic proteins into peptides that are subsequently presented by class I MHC molecules
• Another pair of genes, called HLA-DMA and HLA-
DMB, encodes a nonpolymorphic heterodimer class II-
like molecule, called HLA-DM that is involved in
peptide binding to class II molecules
• Between the class I and class II gene clusters are
genes that code for several components of the
complement system, for three structurally related
cytokines (TNF, lymphotoxin A, and lymphotoxin B),
and for some heat shock proteins
• The genes that encode these diverse proteins have
been called class III MHC genes
• Between HLA-C and HLA-A are many genes that are called the class I-like molecules because they resemble class I genes but they exhibit little or no polymorphism
• Some of these proteins are class IB, among the class IB molecules is HLA-G and HLA-H
• It also contains many pseudogenes
• There are β2 microglobulin -associated proteins other than MHC class I, these include the neonatal FC receptor and CD1 molecules
A more detailed look at MHC
kb
Class I Molecules
• MHC I class molecules are 45-kDa, single-chain glycoproteins that form a complex with 12-kDa β2 microglobulin
• Co-dominantly expressed genes at each of the three distinct “classical” class I loci, HLA-A, -B, and –C are highly polymorphic with over 100 possible alleles at each locus
• Up to six different class I molecules, two for each locus, are displayed on the surface of each nucleated cell
HLA Classe I
• All MHC class I molecules fold to produce a cleft that holds a peptide of eight to eleven amino acids, although the three dimensional configuration of the cleft are somewhat variable
• Some peptides load into clefts of some MHC class I molecules better than others which has major implications in the nature of the immune response
• In addition, a number of molecules (e.g. HLA-E, F, G, H) are structurally similar to classical MHC class I molecules, but are of much more limited variability and tissue distribution
• The functions of nonclassical MHC class I molecules are not yet fully clear, but in some cases they present carbohydrate as well as peptide fragments to gδ
T cells
MHC antigen-binding sites
Class II MHC Molecules• Expressed on few cell types: dendritic cells,
macrophages, B-cells, some epithelial cells of the
thymus, and by some activated T-cells
• Class II molecules are encoded by genes within the
DP, DQ, and DR regions of MHC
• Contained within each region are a and β loci (DPa,
DPβ, DQa, DQβ, DRa, and DRβ)
• After synthesis, MHC class II a and β chains associate
only with others encoded within the same region
HLA Class II
• In combination, the 32-to-38 kDa a and 29-to-32 kDa
β chains form a molecular complex that is very similar
to that of the class I complex, with a binding groove
available for holding short peptides
• The ends of the binding grooves of class II molecules
are more open than class I molecules and can
accommodate peptides of 18 to 20 amino acids in
length
• Like class I molecules, Class II molecules are highly
variable, and numerous allelic forms exist for each
locus (except DRa, which appears to be invariant)
• Genetic variation among class II molecules creates a
range of subtly varying binding grooves for which
antigen fragments compete
• An additional form of variation is available to class II
molecules because of their heterodimeric structure
• Termed cis- trans complementation, this diversity
stems from the fact that class IIa and β chains
combine after synthesis
• Thus, a DPa chain derived from a paternal
chromosome may combine with either DPβ chain
derived from a paternal or maternal chromosome
• Therefore, individuals heterozygous for both
DPa and DPβ (a common situation, given the
high level of variation in these genes) can
produce a greater range of class II dimer
combination than if they were homozygous at
DPa or DPβ or at both
• The range of different MHC I and MHC II
molecules expressed can affect the overall
immune capacity of an individual
Class III MHC Molecules
• Class III molecules are a subset of the
components of serum complement and
cytokines
• The C2 and C4 components, as well as the
regulatory factor B (BF) are encoded within the
complex
• The various components of complement are
synthesized by a variety of cells
Expression of MHC molecules
• Class I molecules are constitutively expressed on virtually all nucleated cells, whereas class II molecules are normally expressed on only dendritic cells, B lymphocytes, macrophages, and a few other cell types
• The expression of MHC molecules is increased by cytokines produced during both innate and adaptive immune responses
• IFNα, β, and g increase MHC class I expression
• IFNg increases the expression of MHC class II by macrophages and vascular endothelial cells and IL-4 by B cells
Properties of MHC
• Polymorphism: The most polymorphic genes; large number of alleles in each locus
• Co-dominance of gene expression: both alleles inherited are expressed maximizing the number of MHC molecules available for binding peptides for presentation to T cells
• The set of MHC alleles on each chromosome is called MHC haplotype which are commonly inherited together (more frequently than would be predicted by random assortment, a phenomenon called linkage disequilibrium)
MHC class I and class II are polymorphic [variability at a gene
locus at a frequency higher than predicted by chance (i.e., variability of alleles
in the species)]
The number of known alleles at various MHC
loci seems to increases over time (why?)
(62)
(80)
(89)
(108)
(8)
(12)
(19)
(20)
(25)
(35)
(45)
(56)
(16)
(20)
(20)
(25)
(122)
(239)
(323)
(440)
(111)
(207
)
(395
)
(559
)
1996
1999
2001
2004
2007Data in
our book
is from
2007
(37)
(50)
(93)
(150
)
(59)
(95)
(195
)
(303
)
(2)
(3)
MHC class I
MHC I a chainDPB, DQB and DRB
are the MHC II b
chain
DPA, DQA and DRA
are the MHC II a chain
MHC is
polymorphic and
expression is co-
dominant
What does this mean
for you and your
species?
for example, here is HLA
class I A gene expression
Although there
are thousands of
combinations in
the population*,
there are only 4
combinations
among siblings
414 known HLA-A alleles in humans (previous slide) but a maximum of 2 per person
Ab/r Ay/g
Ab/g Ar/y Ab/y Ar/g
*At A there are 414
known alleles so
there are (414)2 =
171,396 pair
combinations
possible in the
species (although
not all combinations
exist)
Because MHC
loci are
polymorphic,
individuals are
rarely
homozygous at
any of the
(polygenic) MHC
class I and II loci
Lots of
alleles in the
species In an individual,
several non-allelic
genes with essentially
the same function (B,
C and A are all MHC
class I and present
peptides to CTLs)
Ar
Ay
Br Cy Ap
Br Cy Ap
All expressed on
all nucleated cells
(co-dominant)
Major Histocompatibility Complex
• The major function of the molecules encoded by the MHC is to facilitate the display of unique molecular fragments on the surface of cells in an arrangement that permits their recognition by immune effectors such as T-lymphocytes.
Major Histocompatibility Complex
• The MHC molecule
accomplishes its major role in
immune recognition by
satisfying two distinct
molecular functions: the
binding of peptides (or in
some cases nonpeptidic
molecules) and the interaction
with T cells, usually via the αβ
T-cell receptor (TCR).
MHC I• In particular, cell surface MHC class I glycoproteins gather from the cell’s biosynthetic pathway fragments of proteins derived from infecting viruses, intracellular parasites, or self molecules, either normally expressed or dysregulated by tumorigenesis, and then display these molecular fragments at the cell surface.
Major Histocompatibility Complex (MHC):
A Summary
“A complex of genes encoding cell-surface
molecules that are required for antigen
presentation to T-cells…”
• Fundamentally important:– basis of self / not self distinction– presentation of processed antigen
• MHC-I (on nearly all nucleated cells)
MHC-II (on B-cells, macrophages, dendritic cells)
Major histocompatibility antigens
• MHC loci are highly polymorphic
• Many alternative alleles at a locus
• The loci are closely linked to each other
• A set of alleles is called a HAPLOTYPE
• One inherites a haplotype from mother and
another from father
• The alleles are codominantly expressed
What are the genetic mechanisms?
Nota bene: whatever are the genetic mechanisms, they must account for the huge diversity of “haplotypes”
“Haplotype”: “the set of alleles of linked genes present on one parental chromosome…” synteny
“Synteny”: the association of genes in a distinct region of a chromosome
What are the genetic mechanisms?
• Polygenecity
• Polymorphism
• Co-dominance
• Linkage disequilibrium
What does the “syntenic” organization
of a haplotype look like?
Remember:
polygenecity
polymorphism
co-dominance
Linkage disequilibrium
There are no rearrangements!
What is polygenecity?• Humans have DP, DQ, and DR “regions”
specifying a and b chains of MHC-II.
• Why are these called “regions”?
Inheritance of MHC alleles
Mother Father
A/B C/D
A/C A/D B/C B/D A/R1 R2/C R2/R1
R1=C-D recombination
R2=A-B recombination
Possible children of parents with HLA haplotype A/B and C/D
MHC genes control immune responsiveness
to protein antigens• For almost 20 years after the MHC was discovered, its
only documented role was in graft rejection
• This was a puzzle to immunologists because transplantation is not a normal phenomenon, and there was no obvious reason why a set of genes should be preserved through evolution if the only function of the genes was to control the rejection of foreign tissue grafts
• In the 1960’s and 1970’s, it was discovered that MHC genes are of fundamental importance for all immune responses to protein antigens
• This responsiveness was shown to be inherited
as a dominant trait and the relevant genes were
called immune response (IR) genes and they
were all found to map to the MHC
• We now know that IR genes are in fact MHC
genes that encode MHC molecules which differ
in their ability to bind and display peptides
derived from various protein antigens
Binding of Peptides to MHC
Molecules• For a protein to be immunogenic in an individual, it
must contain peptides that can bind to the MHC
molecules of that individual
• It has become apparent that the binding of peptides to
MHC molecules is fundamentally different from the
binding of antigens to the antigen receptor of B and T
lymphocytes
• MHC molecules show a broad specificity for peptide
binding, and the fine specificity of antigen recognition
resides largely in the antigen receptors of T-cells
• Each class I or class II MHC molecule has a
single peptide-binding cleft that can
accommodate many different peptides
• It is not surprising that a single MHC molecule
can bind multiple peptides because each
individual contains only a few different MHC
molecules (6 for class I and 10-20 for class II
molecules in a heterozygous individual)
• These molecules must be able to present
peptides from the enormous number of protein
antigens that one is likely to encounter
• The peptides that bind to MHC molecules share structural features that promote this interaction
• One of these features is the size (class I accommodate 8-11 amino acids whereas class II can accommodate 10-30 residues long)
• Another factor is the presence of certain amino acid residues that bind certain allelic forms of an MHC-molecule that allows complementarity.
• These residues are distinct from those recognized by TCR
• The association of antigenic peptides and MHC molecules is a saturable, low affinity interaction with a slow on-rate and a very slow off-rate
• Once bound, peptides may remain associated for hours to many days ensuring interactions with antigen-specific T-cells, however, binding is noncovalent
• The MHC molecules of an individual do not discriminate between foreign peptides and peptides derived from self
MHC Supertypes
• Many of the different HLA molecules have similar specificities
• HLA molecules with similar specificities can be grouped together
• Methods to define supertypes
• Structural similarities
• Primary (sequence)
• Tertiary (structure)
• Shared peptide binding motifs
• Identification of cross-reacting peptides
• Ability to generate methods that can predict cross-binding peptides
HLA polymorphism - supertypes
• Each HLA molecule within a supertype binds essentially the same peptides
•Nine major HLA class I supertypes have been defined
• HLA-A1, A2, A3, A24,B7, B27, B44, B58, B62
Supertypes Phenotype frequencies
83 % 86 % 88 % 88 % 86 % 86%
+A1, A24, B44 100 %98 % 100 % 100 % 99 % 99 %
+B27, B58, B62 100 %100 % 100 % 100 % 100 % 100 %
HLA polymorphism - frequencies
MHC: CD Interaction
- The nonpolymorphic Ig-like domains of MHC
molecules contain sites for the T cell molecules
CD4 and CD8 (a3 in class I and β2 in class II)
- A loop in β2 segment of class II molecules is
the binding site for CD4 similar to the binding
site of CD8 to a3 of class I
MHC class I MHC class II
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