Mhc

Major Histocompatibility Complex

Major Histocompatibility Complex: History • Transplantation: graft rejection • Highly polymorphic • Bind peptide: recognized by T cells

Major Histocompatibility Complex (MHC) • MHC are peptide receptors that bind short antigenic peptides on the surface of antigen presenting cells and present them to the T-cell receptors on the cell surface. • 2 classes are distinguished: Class I and Class II. • High diversity. • MHC-peptide binding is allele specific.

Structure of Class I MHC α1 NH2 NH2 Alloantigenic sites

α2

β2

NH2

COOH

CHO

α3

Disulfide bridge

Papain cleavage

Plasma membrane OH

P

Cytoplasm COOH

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 •

Structure of Class I MHC (continued) 3. Transmembrane region – stretch of amino acids spanning membrane 4. Cytoplasmic region – contains sites for phosphorylation

Structure of Class I MHC α1 NH2 NH2 Alloantigenic sites

α2

β2

NH2

COOH

CHO

α3

Disulfide bridge

Papain cleavage

Plasma membrane OH

P

Cytoplasm COOH

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

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 •

Structure of Class II MHC (continued) 3. Transmembrane region – stretch of hydrophobic amino acids spanning membrane 4. Cytoplasmic region – contains sites for phosphorylation

Structure of Class II MHC NH2

NH2

CHO

α1

β1

CHO

α2

β2

CHO

Plasma membrane Cytoplasm COOH COOH

Structure of Class II MHC NH2

NH2

CHO

α1

β1

CHO

α2

β2

CHO

Plasma membrane Cytoplasm COOH COOH

Peptide-binding grooves for class I and class II MHC are structurally similar • 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; openended 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

• MHC class I and class II molecules differentially bind CD8 and CD4 cell adhesion molecules. • MHC class I molecules specifically bind CD8 molecules expressed on cytotoxic T lymphocytes(Tc). • MHC class II molecules specifically bind CD4 molecules expressed on helper T lymphocytes(Th)

Aspects of MHC 1. MHC molecules are membrane-bound. Recognition by T cells requires cell-cell contact. 2. Endogenous antigen associates with class I MHC and is recognized byCD8+ Tc cells. Exogenous antigen associates with class II MHC and is recognized by CD4+Th cells.

Aspects of MHC (continued) A peptide must associate with a given MHC of that individual, otherwise no immune response can occur. That is one level of control.

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.

Aspects of MHC (continued) 6. MHC polymorphism is determined only in the germline. 7. Cytokines (especially interferon-γ) increase level of expression of MHC.

Aspects of MHC (continued) 8 Alleles for MHC genes are co-dominant. Each MHC gene product is expressed on the cell surface of an individual nucleated cell. • Why the high degree of polymorphism? Survival of species!

Accessory Molecules Involved in Cell-Cell Interactions T cell surface molecules that engage with ligand on 2nd cell when TCR recognizes MHC-peptide T Cell Ligand on 2nd Cell CD4 class II MHC (β2 domain) CD8 class I MHC (α3 domain) LFA-2 LFA-3 LFA-1 ICAM-1, ICA-2 LFA = Leukocyte Function-associated Antigen ICAM = InterCellular Adhesion Molecule

Interactions of Th Cell and APC T LFA-2 LFA-1 TCR helper lympho cyte IL-1 IL-6 TNF-alpha IL-12 IL-15

pepti de

CD28

CD4

TNF-beta IFN-gamma GM-CSF IL-4

Antigen- LFA-3 ICAM-1Class II B7-1/B7-2 presenti MHC (CD80/CD86 ng

Interactions of Tc Cell and Target Cell T cytotoxi c lympho cyte

LFA-1

TCR

CD8

pept ide

Target cell

ICAM-1

LFA-2

Class I MHC

LFA-3

Differential cell-type expression of class I and class II molecules correlates with the specialized functions of different types of immune cells

• MHC class I expression is widespread on virtually every cell of the body. This is consistent with the protective function of cytotoxic TC lymphocytes which continuously survey cell surfaces and kill cells harboring metabolically active microorganisms.

• MHC class II expression is restricted to "antigen presenting cells." This is consistent with the functions of helper TH lymphocytes which are locally activated wherever these cells encounter macrophages, dendritic cells, or B cells that have internalized and processed antigens produced by pathogenic organisms.