Chapter 7. 주조직적합성 복합체 1. 주조직적합성 복합체 (MHC)의 발견 2. MHC 분자의 구조 - MHC (Major histocompatibility complex): gene complex responsible for rejection process - Two different MHC classes: class I and class II - Peptides from extracellular protein bind to MHC class II helper T cell recognize the complex - Peptides from intracellular protein bind to MHC class I cytotoxic T cell recognize the complex 1) Mouse - Histocompatibility-2 (H-2): chromosome 17 - K, D, and L region: encode MHC class I - I region (I-A and I-E): encode MHC class II 2) Human - Human leukocyte antigen (HLA): chromosome 6 - A, B, and C region: encode MHC class I - D region (D-P, D-Q, and D-R): encode MHC class II 2. MHC 분자의 구조 1) MHC class I molecule - Present on the surface of all the nucleated cells - consist of  chain (44-47 kDa) and β chain (12 kDa) -  chain: encoded by MHC - β chain (β2-microglobulin): non-MHC coded -  chain is divided into four separate regions: peptide-binding region, Ig-like region, transmembrane region and cytoplasmic region a) The peptide-binding region - 1 and 2 domain of  chain - 1 domain: consist of one  helix and four β-pleated sheets - 2 domain: consist of one  helix and four β-pleated sheets

- Two  helices and eight β sheets form a cleft - The cleft: appropriate size (25Å x 10Å x 11Å) to bind a 9-11 amino acid peptide - 1 and 2 domains are polymorphic - Interact with TcR of Tc cell b) The immunoglobulin-like region - Consist of 3 domain of  chain and β2-microglobulin - folded to form Ig-like domains - Non-polymorphic - 3 domain interacts with CD8 of T cell - Interaction of β2-microglobulin with 1, 2, and 3: critical for maintaining native structure c) The transmembrane region - 25 aa residue stretch of hydrophobic amino acids form an  helix pass through the hydrophobic membrane d) The cytoplasmic region - C-terminal 30 aa residue - Has consensus phosphorylation site for protein kinase A and pp60 src tyrosine kinase 2) MHC class II molecule - Present on the surface of macrophage, B cell, dendritic cell, endothelial cell and epithelial cell of thymus - Consist of  chain (32-34 kDa) and β chain (29-32 kDa) -  and β chains are divided into four separate regions: peptide-binding region, Ig-like region, transmembrane region and cytoplasmic region a) The peptide-binding region - Consist of 1 domain of  chain and β1 domain of β chain - 1 domain: consist of one  helix and four β-pleated sheets - β1 domain: consist of one  helix and four β-pleated sheets - The cleft: appropriate size to bind about 15 amino acid peptide - β1 is polymorphic - Interact with TcR of TH cell

3. MHC의 유전자 구성 b) The Ig-like region - Consist of 2 domain of  chain and β2 domain of β chain - Non-polymorphic - β2 domain interact with CD4 of T cell c) The transmembrane and cytoplasmic regions - Transmembrane region: 25 hydrophobic aa residue - cytoplasmic region: short, hydrophilic tail 3. MHC의 유전자 구성 1) MHC 유전자좌의 구성 - Human: chromosome 6 - Occupies a large segment of DNA, extending about 3500 kbp a) The MHC class I - MHC class I: encoded by A, B, C - A heterozygous individual expresses six different polymorphic alleles ( three from each parent) and six MHC class I molecules per cell - Class I-like: coded by F, G, H, J and X function as an Fc receptor for IgG b) The MHC class II - MHC class II: coded by DP, DQ, DR - Usually 2-3 functional β chain genes for some class II loci but usually only one  chain gene - Individuals can express 10 to 20 different class II gene products per cell

4. MHC 분자의 발현 조절 1) The constitutive expression of class I molecule is distinct from that of class II molecules - MHC class I: all nucleated cells - MHC class II: B cell, macrophage, dendritic cells, endothelial cells 2) Cytokines can modulate the rate of transcription of class I and class II genes a) MHC class I - γ-interferon (IFN-γ): increase the level expression of class I molecules - IFN-, IFN-β and TNF (tumor necrosis factor): also increase class I molecule expression b) MHC class II - macrophage: IFN-γ increase class II expression but IFN-, IFN-β and IL-10 decrease class II expression - Endothelial cell: IFN-γ increase class II expression - B cells and lymphoid dendritic cells: constitutively express class II molecule