Major histocompatibility complex and antigen presentation & processing

MAJOR HISTOCOMPATIBILITY
COMPLEX AND ANTIGEN
PROCESSING AND PRESENTATION
PRESENTER : J. AISHWARYA
M.Sc. 3RD YEAR MEDICAL BIOCHEMISTRY
18-May-21
1

 How the MHC was discovered using inbred strains of mice
 General Organization and Inheritance of the MHC
 MHC Molecules and Genes
 Detailed Genomic Map of MHC Genes
 Cellular Distribution of MHC Molecules
 Structure, Function relationship of MHC molecules
 Regulation of MHC Expression
 The meaning of polymorphism and polygenism in the MHC
 MHC and Immune Responsiveness
 MHC and Disease Susceptibility
18-May-21 3

Transplant rejection
 Early attempts to transplant tissues – failed!
 Rejection of transplanted tissue - associated with inflammation and lymphocyte
infiltration
 In1940s, to analyze the genetic basis of graft rejection,- produced inbred mouse
strains by repetitive mating of siblings
 Inbred mice are homozygous at every genetic locus (i.e., they have two copies of the
same allele of every gene, one from each parent), and every mouse of an inbred strain
is genetically identical (syngeneic) to every other mouse of the same strain
 IMMUNE
GRAFT REJECTION
18-May-21 5

 Why rat and mouse were chosen to study the transplant immunology?
The origin of Immunogenetics
Genetic basis of transplant rejection
18-May-21 6

Immunological basis of graft rejection
18-May-21 7

Immunogenetics of graft rejection
18-May-21 8

 Demonstrated - single genetic region on chromosome 17 - primarily
responsible for rapid rejection of tissue grafts - major histocompatibility locus
 The particular locus that was identified in mice contained a gene encoding a
blood group antigen called antigen II, and therefore, this region was named
histocompatibility-2, or simply H-2
 Initially thought - only a single gene controlled transplant rejection
 Occasional recombination - within the H-2 locus during interbreeding of
different strains- indicated it contained several different but closely linked
genes, many of which were involved in graft rejection
 The genetic region that controlled graft rejection and contained several linked
genes was named the Major histocompatibility complex
18-May-21 9

 The human MHC - discovered by searching for cell surface molecules in one
individual that would be recognized as foreign by another individual
 The proteins recognized by these antibodies were called human leukocyte
antigens (HLA)
 leukocyte because the antibodies were tested by binding to the leukocytes of other
individuals, and
 antigens because the molecules were recognized by antibodies
 Only monozygous twins are identical at the HLA locus
 The human population is extensively out bred
 MHC genetics in humans is extremely complex
18-May-21 10

 After 20 years of discovery – documented role in transplant
rejection
 Puzzled immunologists – stated that transplantation being an
artificial phenomenon, cannot have conserved through time
 Other putative roles
 Now documented roles – Immune response
 Scientists - Inbred strains of a single species (guinea pigs or
mice) differed in their ability to make antibodies against some
simple polypeptides, and responsiveness was inherited as a
dominant Mendelian trait.
 The relevant genes were called immune response (Ir) genes,
and they were all located in the MHC.
 Ir genes are, in fact, MHC genes that encode MHC molecules -
differ in their ability to bind and display peptides derived from
various protein antigens
18-May-21 11

General Organization and Inheritance of the MHC
 Major Histocompatibility Complex
 Cluster of genes found in all mammals
 Its products play role in discriminating self/non-self
 Participant in both humoral and cell-mediated immunity
 MHC Act As Antigen Presenting Structures
 In Human MHC Is Found On Chromosome 6
 Referred to as HLA complex
 In Mice MHC Is Found On Chromosome 17
 Referred to as H-2 complex
18-May-21 12

MHC Genes
 The MHC locus contains two types of polymorphic MHC genes, the class I and class
II MHC genes, which encode two groups of structurally distinct but homologous
proteins, and other nonpolymorphic genes whose products are involved in antigen
presentation
 The polymorphic class I and class II MHC molecules - function is to display peptide
antigens for recognition by CD8+ and CD4+ T cells, respectively.
 The nonpolymorphic molecules encoded in the MHC do not present peptides for T cell
recognition
 Different human class I HLA molecules - distinguished by serologic approaches
(antibody binding)
 Different class II MHC molecules - identified by use of assays in which T cells from
one individual would be activated by cells of another individual (called the mixed
lymphocyte reaction
 Currently - DNA sequencing is used to distinguish different MHC alleles and their
encoded proteins 18-May-21 13

SHORT ARM OF
CHROMOSOME 6
CHROMOSOME
17
18-May-21 14

 The variations in MHC molecules (accounting for the polymorphism) result from
inheritance of distinct DNA sequences - not induced by gene recombination
 Because the products of different MHC alleles bind and display different peptides,
different individuals in a population may present different peptides even from the
same protein antigen.
 MHC polymorphism may have evolved because - it ensures that human
populations will be able to deal with the virtually unlimited diversity of microbes
and will be protected from devastating loss of life from emerging infections.
18-May-21 15

The MHC Encodes Three Major Classes of Molecules
Genes Of MHC Organized In 3 Classes
 Glycoproteins expressed on all nucleated cells
 Major function to present peptide Ags to TC
Glycoproteins expressed on M , B-cells, DCs
 Major function to present processed Ags peptides to TH
 Class III molecules are not membrane proteins, are not related structurally to class I
and class II molecules, and have no role in Ag presentation
 most play some role in immune responses. e.g., C2, C4a, C4b, factor B, 21-
hydroxylase enzymes, TNFα, TNFβ, heat shock proteins (HSP)( include
secreted proteins)
Class I MHC genes
Class II MHC genes
Class III MHC genes
18-May-21 16

SIMPLIFIED
ORGANISATION
OF MHC IN
MOUSE AND
HUMAN
18-May-21 17

 There are three class I MHC genes - HLA-A, HLA-B, and HLA-C, which encode three
types of class I MHC molecules
 Three class II HLA gene loci called HLA-DP, HLA-DQ, and HLA-DR.
 Each class II MHC molecule is composed of a heterodimer of α and β polypeptides.
 The DP, DQ, and DR loci on each chromosome contain separate genes designated A
and B, encoding the α and β chains, respectively.
CLASS I
MHC
CLASS II
MHC
18-May-21 18

 Every individual has
 two HLA-DP genes
DPA1 and DPB1)
 two HLA-DQα genes
(DQA1, 2),
 one HLA-DQβ gene
(DQB1),
 one HLA-DRα gene
(DRA1), and
 one or two HLA-DRβ
genes (DRB1 and DRB3 ,
4, or 5).
18-May-21 19

1. Allelic Forms of MHC Genes Are Inherited in Linked Groups Called Haplotypes
 The loci constituting the MHC are highly polymorphic - many alternative forms of the gene, or
alleles, exist at each locus among the population.
 The genes of the MHC loci lie close together
 Most individuals inherit the alleles - as two sets, one from each parent.
 Each set of alleles is referred to as a haplotype
 An individual inherits one haplotype from the mother and one haplotype from the father.
2. The alleles are co-dominantly expressed - both maternal and paternal gene products are
expressed in the same cells
this maximizes the number of MHC molecules available to bind peptides for
presentation to T cells.
18-May-21 20

 The mouse MHC, located on chromosome 17
 One of the mouse class I genes (H-2K) is centromeric to the class II region, but the other class I genes
are telomeric to the class II region
 Three mouse class I MHC genes called H-2K, H-2D, and H-2L, encoding three different class I MHC
proteins, K, D, and L
 Mice have two class II MC loci called I-A and I-E, which encode the I-A and I-E molecules
18-May-21 21

SKIN TRANSPLANTATION
BETWEEN SAME OR
DIFFERENT MHC
HAPLOTYPES
18-May-21 24

Differential distribution of MHC molecules
18-May-21 25

STRUCTURAL ORGANISATION OF
MHC MOLECULE
18-May-21 26

 Each MHC molecule consists of an extracellular peptide-binding cleft, followed by an
immunoglobulin (Ig)–like domain and transmembrane and cytoplasmic domains
 The polymorphic amino acid residues of MHC molecules are located in and adjacent to the
peptide-binding cleft – wall alpha helices and floor – beta pleated sheets
 The nonpolymorphic Ig-like domains - contain binding sites for the T cell molecules CD4
and CD8
 CD4+ helper T cells recognize class II MHC molecules displaying peptides, whereas CD8+
T cells recognize class I MHC molecules with bound peptides
 Stated differently, CD4+ T cells are class II MHC restricted and CD8+ T cells are class
I MHC restricted
18-May-21 27

Cell Membrane
Peptide
MHC class I MHC class II
MHC molecules
Peptide
binding groove
18-May-21 28

Class I Molecules Have a Glycoprotein
Heavy Chain and a Small Protein Light Chain
 MHC-encoded - α chain of 43kDa ,Made Up
Of 3 Domains ( α1, α2 and α3)
 β 2-microglobulin, 12kDa, non-MHC encoded,
non transmembrane, non covalently bound to
α -3 domain
 The α 3 segment of the MHC I , is highly
conserved among MHC1 - serves as a
binding site for CD8
 Peptide antigen in a groove formed from a
pair of α helicies on a floor of anti-parallel b
strands
 α -chain anchored to the cell membrane
 The chain the HLA-A, -B, -C and 2m on
different chromosome
18-May-21 29

 α 1, α 2 and α 3 contains 90 amino acid ,
 tm domain 25 hypho AA,
 followed by short stretch of hyphi AA and
 cytoplasm anchor of 30 AA
 α 3 domain & β 2m have structural & amino
acid sequence homology with Ig C domains -
Ig GENE SUPERFAMILY
 Association Of α Chain and β 2m Is Required
For Surface Expression
Duadi tumours
 absence β 2-m , cell is unable to express MHC
1 on the membrane
18-May-21 30

 α 1 and α 2 domains form
two segmented α -helices
on eight anti-parallel β -
strands to form an antigen-
binding cleft.
 Properties of the inner faces
of the helices and floor of
the cleft determine which
peptides bind to the MHC
molecule
 The formed cleft can bind
peptides of 8 -10 amino
acids in a flexible extended
conformation.
The fully assembled class I molecule is a trimeric
complex consisting of an α chain, β2-
microglobulin, and a bound peptide, and stable
expression of class I molecules on cell surfaces
requires the presence of all three components of
the complex 18-May-21 31

 MHC-encoded, α -chain of 34kDa , α 1 and α 2 and a β -
chain of 29kDa 1 and 2
 No β -2 microglobulin
 α and β chains anchored to the cell membrane
 These chains are non-covalently associated peptides
 Peptide antigen in a groove formed from a pair of α -
helices on a floor of anti-parallel β strands
 α 2 & β 2 domains have structural & amino acid sequence
homology with Ig C domains - Ig GENE SUPERFAMILY
18-May-21 32

 Class II Molecules Have Two Nonidentical Glycoprotein Chains
 • CD4 Molecule Binds α 2/ β 2 domains
 The α chains are the HLA DR
 The β chains are the HLA DQ and DP
 The fully assembled class II MHC molecule is a trimer
consisting of one α chain, one β chain, and a bound antigenic
peptide, and stable expression of class II molecules on
cell surfaces requires the presence of all three components
of the complex.
18-May-21 33

Features of Class I and Class II MHC molecules
18-May-21 34

 A binding site that is flexible enough to bind any peptide?
 NO because: at the cell surface, such a binding site would be unable to
 • allow a high enough binding affinity to form a trimolecular complex with the T cell
antigen receptor
 • prevent exchange of the peptide with others in the extracellular milieu
A flexible binding site?
18-May-21 39

 A binding site that is flexible at an early, intracellular stage of maturation Formed
by folding the MHC molecules around the peptide.
 Allows a single type of MHC molecule to
 • bind many different peptides
 • bind peptides with high affinity
 • form stable complexes at the cell surface
 • Export only molecules that have captured a peptide to the cell surface
Floppy Compact
18-May-21 40

 Several hundred different allelic variants of class I and II MHC molecules - identified in
humans.
 Any one individual - expresses only a small number of these molecules— up to 6 different
class I molecules and up to 12 different class II molecules.
 Yet this limited number of MHC molecules must be able to present an enormous array of
different antigenic peptides to T cells, permitting the immune system to respond specifically to
a wide variety of antigenic challenges
18-May-21 41

COMMON FEATURES OF MHC – PEPTIDE INTERACTION -
 MHC molecules show a broad specificity for peptide binding, in contrast to the fine specificity
of antigen recognition by the antigen receptors of lymphocytes
 Each class I or class II MHC molecule has a single peptide-binding cleft that binds one peptide
at a time, but each MHC molecule can bind many different peptides
 The peptides that bind to MHC molecules share structural features that promote this
interaction.
 MHC molecules acquire their peptide cargo during their biosynthesis and assembly inside cells
 The association of peptides and MHC molecules is a saturable interaction with a very slow off-
rate
 Very small numbers of peptide-MHC complexes are capable of activating specific T
lymphocytes
 The MHC molecules of an individual can bind and display foreign peptides (e.g., those derived
from microbial proteins) as well as peptides derived from the proteins of that individual (self
antigens). 18-May-21 42

 Class I MHC molecules bind peptides and present them to CD8+ T cells
 Peptides are derived from endogenous intracellular proteins that are digested in the
cytosol
 The peptides are then transported from the cytosol into the cisternae of the endoplasmic
reticulum, where they interact with class I MHC molecules.
This process, known as endogenous processing pathway
18-May-21 43

 The bound peptides isolated from class I molecules found to have two distinguishing
features:
1. they are eight to ten amino acids in length, most commonly nine, and
2. they contain specific amino acid residues that appear to be essential for binding to a
particular MHC molecule.
 Binding studies have shown - nonameric peptides bind to class I molecules with a
100- to 1000-fold higher affinity than do peptides that are either longer or shorter, -
most compatible with the closed-ended peptide-binding cleft in class I molecules.
 The ability of an individual class I MHC molecule to bind to a diverse spectrum of
peptides is due to the presence of the same or similar amino acid residues at several
defined positions along the peptides
 Because these amino acid residues anchor the peptide into the groove of the MHC
molecule, they are called anchor residues.
 The side chains of the anchor residues in the peptide are complementary with surface
features of the binding cleft of the class I MHC molecule.
18-May-21 45

18-May-21 56
Molecular basis of MHC types and variants

Errors in the
inheritance of
haplotypes
generate
polymorphism
in the MHC by
gene
conversion and
recombination
18-May-21 60

Major histocompatibility complex and antigen presentation & processing

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