mhc lecture notes
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TRANSCRIPT
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Prof M.I.N. MateeMicrobiology and Immunology
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Significance of the MHCSignificance of the MHC
role in immune response role in organ transplantation role in predisposition to disease
role in immune response role in organ transplantation role in predisposition to disease
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Major Histocompatibility Complex: History Transplantation: graft rejection Immune responses: antibody
formation Highly polymorphic Bind peptide: recognized by T cells Three-dimensional structure
determined by X-ray crystallography
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Structure of Class I MHC
NH2
Alloantigenicsites
CHO
NH2
COOH
COOH
P
α1
α2
α3
β2
OH
Plasma membrane
Disulfide bridge
Papain cleavage
Cytoplasm
NH2
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Structure of Class I MHC
Two polypeptide chains, a long α chain and a short β chain, called β2 microglobulin
Four regions:1. Peptide-binding region - a groove
formed from α1 and α2 domains of the α chain
2. Immunoglobulin-like region – highly conserved α3 domain - site to which CD8 on T cell binds
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Structure of Class I MHC(continued)
3. Transmembrane region – stretch of hydrophobic amino acids spanning membrane
4. Cytoplasmic region – contains sites for phosphorylation and binding to cytoskeletal elements
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Structure of Class I MHC
NH2
Alloantigenicsites
CHO
NH2
COOH
COOH
P
α1
α2
α3
β2
OH
Plasma membrane
Disulfide bridge
Papain cleavage
Cytoplasm
NH2
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Structure of Class I MHC Peptide-binding Region a “groove” composed of an α-helix on
two opposite walls and eight β-pleated sheets forming the floor
residues lining groove most polymorphic
peptide in groove 8-10 amino acids long specific amino acid on peptide required
for “anchor site” in groove
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Variability For Polymorphism
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Structure of Class II MHC
Plasma membrane
Cytoplasm
CHO
CHO
CHO
NH2 NH2
COOH COOH
α1
α2 β2
β1
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Structure of Class II MHC Two polypeptide chains, α and β, of
roughly equal length. Four regions:1. Peptide-binding region – a groove
formed from the α1 and β1 domains of the α and β chains – site of polymorphism
2. Immunoglobulin-like region – conserved α2 and β2 domains – β2 is site to which CD4 on T cell binds
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Structure of Class II MHC(continued)
3. Transmembrane region – stretch of hydrophobic amino acids spanning membrane
4. Cytoplasmic region – contains sites for phosphorylation and binding to cytoskeletal elements
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Structure of Class II MHC
Plasma membrane
Cytoplasm
CHO
CHO
CHO
NH2 NH2
COOH COOH
α1
α2 β2
β1
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Variability For Polymorphism
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Both have a peptide-binding groove with a wall of two α helices and a floor of eight β-pleated sheets
Close-ended groove for class I MHC requires an 8-10 amino acid-length peptide to bind; open-ended groove for Class II MHC lets it bind a peptide 13-25 amino acids long, not all of which lie in the groove
Anchor site rules apply to both classes
Peptide-binding grooves for class I and class II MHC are structurally similar
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Aspects of MHC
1. MHC molecules are membrane-bound. Recognition by T cells requires cell-cell contact.
2. Peptide from cytosol associates with class I MHC and is recognized by Tc cells. Peptide from vesicles associates with class II MHC and is recognized by Th cells.
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Aspects of MHC (continued)3. Although there is a high degree of
polymorphism for a species, an individual has maximum of six different class I MHC products and only slightly more class II MHC products.
A peptide must associate with a given MHC of that individual, otherwise no immune response can occur. That is one level of control.
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Aspects of MHC (continued)4. Mature T cells must have a T cell
receptor that recognizes the peptide associated with MHC. This is the second level of control.
5. Each MHC molecule has only one binding site. The different peptides a given MHC molecule can bind all bind to the same site, but only one at a time.
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Aspects of MHC (continued)6. MHC polymorphism is determined only in
the germline. There are no recombinational mechanisms for generating diversity.
7. Because each MHC molecule can bind many different peptides, binding is termed degenerate.
8. Cytokines (especially interferon-γ) increase level of expression of MHC.
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Aspects of MHC (continued)
9. Alleles for MHC genes are co-dominant. Each MHC gene product is expressed on the cell surface of an individual nucleated cell.
10. Why the high degree of polymorphism?
Survival of species!
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Structure of T Cell Receptor
CHO CHO
CHOCHO
Variable region “V”
Constant region “C”
Hinge “H”
Alphachain
Betachain
Disulfide bridge
Transmembrane region
Cytoplasmic tail
++ +
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Structure of T Cell Receptor (TCR) Two polypeptide chains, α and
β, of roughly equal length Both chains consist of a variable
(V) and a constant (C) region α chain V region has a joining
(J) segment β chain V region has both a J
and diversity (D) segment
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Structure of T Cell Receptor(continued) Hypervariable regions in V
contribute to diversity of TCR TCR recognizes portions of MHC
molecule and peptide bound in the groove
Small population of T cells has a TCR comprised of γ and δ chains – γδ TCR specificity differs from αβ TCR
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Structure of T Cell Receptor
CHO CHO
CHOCHO
Variable region “V”
Constant region “C”
Hinge “H”
Alphachain
Betachain
Disulfide bridge
Transmembrane region
Cytoplasmic tail
++ +
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Accessory Molecules
All are invariant Increase adhesion between two
engaged cells Some show increased expression
in response to cytokines
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Costimulatory Molecules
Molecules on T cell and 2nd cell that engage to deliver 2nd signal required for activation of T cell
Most important costimulatory molecules:
T cell Ligand on 2nd cell
CD28 B7-1 (CD80), B7-2 (CD86)
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Interactions of Th Cell and APC
LFA-3
LFA-2 LFA-1 TCR
CD4
ICAM-1 Class IIMHC
B7-1/B7-2(CD80/CD86
CD28
IL-1IL-6TNF-alphaIL-12IL-15
TNF-betaIFN-gammaGM-CSFIL-4
T helperlymphocyte
Antigen-presenting
cell
peptide
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Interactions of Tc Cell and Target Cell
LFA-1 TCR
CD8
ICAM-1 Class IMHC
LFA-3
LFA-2T cytotoxiclymphocyte
Targetcell
peptide
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The human MHC genesThe human MHC genes
class II c lass ID P D Q D R B C A
B C A
D P D Q D R
1 2 2 2 1 1 9 3 1 2 2 1 3
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Class-I expressed on all nucleated cells in man
Class-II expressed primarily on antigen presenting cells (dendritic cells, macrophages and B cells, etc.)
Differential expression of MHC
antigens
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HLA and disease associationHLA and disease association
Disease Associated alleles Frequency in
Relative riskpatients contro
l
Ankylsoing spondylitis
Reiter’s disease
Acute anterior uveitis
Psoriasis vulgaris
Dermatitis herpetiformis
B27
B27
B27
CW6
DR3
9
79
52
87
85
9
9
9
33
26
87.4
37.0
10.4
13.3
15.4