Major Histocompatibility Complex Part 1 Transcript

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Learning Objectives (Part 1)
• Introduction
• Definition
• Classes of MHC Molecules
• MHC Genes
• Structure of MHC Molecules
• Class I MHC Molecules
• Class II MHC Molecules
• Comparison of Class I & Class II MHC Molecules
• MHC Restriction
Introduction
• Both B cells and T cells use surface molecules to recognize antigens.
• They accomplish this in very different ways.
• B-cell receptors (antibodies) can recognize an antigen alone.
• T-cell receptors can only recognize peptide fragments of protein
antigens that are positioned on the surface of other cells.
• The peptide fragments are held within the binding groove of a
specialized cell surface protein called
"Major Histocompatibility Complex (MHC) Molecule".
Introduction
• Major Histocompatibility Complex (MHC) molecules display peptide
fragments of protein antigens for recognition by antigen-specific T
lymphocytes.
• They were discovered as gene products that induced rejection of
transplanted organs.
• Their name derived from their role in determining the compatibility of
tissue between individuals.
• In humans, MHC molecules are also called Human Leukocyte Antigens
(HLA) as they were first detected on leukocytes by binding of
antibodies.
Introduction
• MHC molecules are fundamental to antigen recognition by T cells.
• Success of tissue and organ transplant depends on MHC molecules of
the donor and recipient.
• MHC molecules are linked to many autoimmune diseases.
• 1980 Nobel Prize in Medicine and Physiology was awarded to
immunologist Benacerraf, Dausset and Mouse Geneticist and
Transplant immunologist George Davis Snell for characterizing the
functions controlled by MHC, particularly organ transplant fate and
immune response to antigen.
Definition
• Major Histocompatibility Complex (MHC) molecules are membrane
glycoproteins that display peptide fragments of protein antigens for
recognition by antigen-specific T lymphocytes.
• Ref. Robbins & Cortan Pathologic Basis of Disease 9th Edition
• The major histocompatibility complex (MHC) molecules are membrane

glycoproteins that act as a cell surface vessel for holding and displaying
fragments of antigen so that approaching T cells can engage with this
molecular complex via their T-cell receptors.
• Ref. Kuby Immunology 7th Edition
Classes of MHC Molecules
• There are two main classes:
• Class I MHC Molecules
• Class II MHC Molecules
MHC Genes
• In human, the genes that encode MHC molecules are clustered on
short arm of chromosome 6 and occupy a large segment of DNA
(extending about 3500 kilobases).
• There are three class I MHC genes called HLA-A, HLA-B and HLA-C.
They encode the three types of class I MHC molecules with the same
name.
• There are three class II MHC gene loci called HLA-DP, HLA DQ and
HLA-DR.
• Each class II MHC molecule is composed of a heterodimer of alpha
and beta polypeptides.
MHC Genes
• The DP, DQ, and DR loci on each chromosome contain separate genes
designated A and B that encode the α and β chains, respectively.
• Every individual has two HLA-DP genes (called 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).
• Every individual has two haplotypes (two sets of these genes).
• One set of genes on the paternal chromosome 6 and the other set of
genes on the maternal chromosome 6.
MHC Genes
• Between the class I and class II gene loci is a third locus

sometimes called class III.
• Class III gene locus encodes tumor necrosis factor,
lymphotoxin, C2, C4 but does not encode
histocompatibility antigens.
Structure of MHC Molecules
• General Properties:
• Each MHC molecule consists of an extracellular peptide-binding cleft,
followed by an immunoglobulin 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.
• The nonpolymorphic Ig-like domains of class I and class II MHC
molecules contain binding sites for the T cell molecules CD8 and CD4,
respectively.
Class I MHC Molecules
• They are expressed on all nucleated cells and platelets.
• They are heterodimers.
• Consists of a polymorphic ɑ chain or heavy chain (44-kD) linked non-
covalently to a smaller nonpolymorphic β2-microglobulin (12-kD).
• ɑ Chains are encoded by HLA-A, HLA-B and HLA-C genes.
• β2-microglobulins are encoded on chromosome 15.
• The extracellular region of the ɑ chain is divided into ɑ1, ɑ2 and ɑ3
domains.
• ɑ1 and ɑ2 domains form a cleft or groove where peptides can bind.
• The sides and base of the peptide-binding grooves are formed by
polymorphic amino acid residues.
• Class I MHC molecules display peptides derived from viral proteins
and tumor antigens, that are located in the cytoplasm of the cells and
are usually produced in the cells.
• The fully assembled class I molecule is a trimeric complex consisting
of an α chain, β2-microglobulin, and a bound peptide.
• Stable expression of class I molecules on cell surfaces requires the
presence of all three components of the complex.
• Class I MHC-associated peptides are recognized by CD8+ T cells.
• The nonpolymorphic ɑ3 domain of class I MHC molecules contain a
binding site for CD8.
Class II MHC Molecules
• They are expressed on the surface of professional antigen-presenting
cells (APCs) such as Dendritic cells, Macrophages and B cells.
• They present antigens that are internalized into vesicles and are
usually derived from extracellular microbes and soluble proteins.
• They are encoded in HLA-D region which has three subregions: HLA-
DP, HLA-DQ and HLA-DR.
• They are heterodimers consisting of a noncovalently associated
polymorphic ɑ chain and β chains.
Class II MHC Molecules
• The extracellular portions of ɑ and β chains both have two domains
that are called ɑ1 and ɑ2, and β1 and β2.
• Peptide binding groove is formed by α1 and β1 domains.
• Most class II alleles differ in this portion (binding groove).
Comparison of Class I & II MHC Molecules
Features Class I MHC Class II MHC

Polypeptide chains α and β2-microglobulin α and β
Location of polymorphic α1 and α2 domains α1 and β1 domains
residues
Size of peptide-binding Accommodates peptides of Accommodates peptides of
groove 8–11 residues 10–30 residues or more
Binding site for T cell CD8 binds mainly to the α3 CD4 binds to a pocket
coreceptor domain created by parts of α2
and β2 domain
Ref. Cellular and Molecular Immunology 9th Edition

MHC Restriction
• T cell's ability to recognize antigens depends on association of the antigen
with self MHC molecules.
• Cytotoxic T cells recognize antigen in association with self class I MHC
molecules.
• Helper T cells recognize antigen in association with self class II MHC
molecules.
• The requirement to recognize antigen in association with a “self ” MHC
protein is called MHC restriction.
MHC Restriction
• B cells do not have such requirement and can recognize

soluble antigens in plasma with their surface monomer
IgM (antigen receptor).

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• The major histocompatibility complex (MHC) molecules are membrane

• Between the class I and class II gene loci is a third locus

Comparison of Class I & II MHC Molecules

Features Class I MHC Class II MHC

Ref. Cellular and Molecular Immunology 9th Edition

• B cells do not have such requirement and can recognize

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