Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
DNA vaccination wikipedia , lookup
Immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Innate immune system wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Adaptive immune system wikipedia , lookup
Human leukocyte antigen wikipedia , lookup
Molecular mimicry wikipedia , lookup
Major Histocompatibility Complex and Antigen Presentation 미생물학교실 권 형 주 Antigen Presentation, MHC-Peptide complex, TCR Medzhitov R, & Janeway C Jr., N. Engl. J. Med., 2000. 343, 338-344 MHC의 발견 - Polymorphic: many alternative forms of the gene, or allele, exist at each locus among the population - Inbred mice: Homozygous at every genetic locus : Every mouse of an inbred strain is genetically completely identical (syngenic) - Congenic mouse strains: a single genetic region is responsible for most rejection phenomena Simplified organization of the MHC in the mouse and human Major Histocompatibility Complex (MHC) molecules - T 세포에 항원을 전달 Recognition by the ab TCR requires antigen to be bound to an MHC molecule : Short peptide fragments (endogeneously synthesized)-MHC class I complex : short peptide fragments (extracellular origin)-MHC class II complex : Peptide-MHC complexes serve as ligands for TCRs MHC molecule provide a sophisticated surveillance system for intracellular antigens : MHC class I molecules - intrinsic antigens 인식 - antigenic peptides from viruses or other pathogens that inhabit the cell - present antigen to cytotoxic T cells (CD8+ T cells) - controlling viral infections by lysing infected cells : MHC class II molecules – extrinsic antigens 인식 - present antigen to helper T cells (CD4+ T cells) - aid B cells in generating antibody responses to extracellular protein antigens : antigenic peptides are produced by proteolytic processing of proteins - Antigen processing and presentation MHC class I and II molecules MHC class I - Glycosylated heavy chain (a-chain, 45 kDa) associated with b2-microglobulin (12 kDa) - Heavy chain : three extracellular domains (a1, a2, a3) : transmembrane domain : cytoplasmic tail : intracellular disulfide bond: a2, a3 : a3 domain-homologous Ig C domain interacts with CD8 Tc cells b2-microglobulin is essential for expression of MHC class I molecules - non-polymorphic in humans - Ig constant region domain - associate with class I-like molecules (CD1, Fc receptor) - The cell surface-mutant mice lacking b2m do not express class I : essential for the expression of all class I molecules - Daudi cells (tumor) : absence of b2m, MHC class I a chain –not in membrane : transfection of b2m –MHC class I appear on membrane MHC class II - Heterodimers: heavy a chains: 30-34 kDa light b chains: 26-29 kDa - Extracellular domains : a1 and a2, b1 and b2 - Peptidie-binding cleft : a1 - b1 - Transmembrane region : ~30 residues - Cytoplasmic domain : 10-15 residues - a2 and b2 domains class I a3 and b2m - a1, a2, b1 domains: N-glycosylated - b2 domain : binding site for CD4 Blue : HLA-DR1 Red : HLA-A2 The exon/intron arrangement of class I and II genes reflects their domain structure Class I and II molecules exhibit polymorphism in the region that binds to peptides Class I MHC-peptide interaction - The bound peptides isolated from cell surface MHC molecules purify and sequence the peptides (HPLC) : foreign peptides – internalized antigens or viral particles : self molecules produced within the cell or endocytosed from extracellular fluids Example of anchor residues (blue) in nonameric peptides eluted from two class I MHC molecules Class II MHC-peptide interaction - Incorporates a number of binding pockets, though the locations are somewhat different from that on class I molecules - Class II Is not closed at the ends, so bound peptides extend out of the ends of the groove - 13-18 amino acids Peptides binding MHC class II are less uniform in size than those binding MHC class I molecules - MHC class II : extend beyond the ends of the cleft = antigen processing pathway (chapter 7) Class I and Class II molecules exhibit diversity within a species, and multiple forms occur in an individual - Ab, TCR diversity : somatic process : gene rearrangement, somatic mutation -MHC : polymorphism : multiple alleles at a given genetic locus within the species : polygenic (HLA-A, -B, and –C) : HLA-A, -B, and –C : 370X660X190, : 46 million different class I haplotypes possible in the population Linkage disequilibrium : the actual diversity is known to be less, because certain allelic combinations occur more frequently in HLA haplotype than predicted by random combination : Successful organ transplants ???? Functional relevance of MHC polymorphism Detailed genomic Map of MHC genes Cellular expression of MHC Molecules - Class I MHC molecules : Expressed on most nucleated cells : Lymphocytes – 5 x 105 molecules/cell : Cell에 따라 발현정도 다름 - Class II MHC molecules : APC, macrophages, mature dendritic cells, thymic epithelial cells…… : Cytokine stimulation, differentiation stage에 따라 다름…… Human class II genes are located in the HLA-D region - HLA-D region, Three loci : DR, DQ, DP - DR family: single a gene (DRA) up to nine b genes (DRB1-9)including pseudogenes - The class II region also contains genes that encode proteins involved in antigen presentation that are not expressed at the cell surface - The organization and length of the DRB region varies in different haplotypes, with different numbers of b chain expressed MHC polymorphism is concentrated in and around the peptide-binding cleft - Extreme degree of polymorphism (structural variability) - Class I : a1 and a2 domains - Class II : DRb, DQa, DQb chains, DPbless polymorphic -- peptide binding site DRa chains are invariant - Individuals have two MHC haplotypes Regulation of MHC Expression - Regulation MHC class II expression - CIITA : class II transcriptional activator CpG-DNA LPS IFN-g TLRs MyD88 JAK1, 2 P Stat1 IRAK p38 MEK-1 ? IRF-1 TRAF6 Stat1 USF-1 CIITA IkB NF-kB c-Rel p65 CIITA NF-Y RFX kB X X2 Y HLA-DRA - Regulation MHC class I expression MHC and Diseases Susceptibility An individual’s MHC haplotype affects their susceptibility to disease Different MHC molecules affect: - The ability to make immune responses, including the level of antibody production - Resistance or susceptibility to infectious disease - Resistance or susceptibility to autoimmune diseases and allergies Why the MHC is so polymorphic? - many different pathogens selective advantage in having different MHC molecules - select for different MHC molecules in each area Self-MHC Restriction of T cells CD4+ and CD8+ T cells can recognize antigen only when presented by a self-MHC molecule - CD4+ TH cell is class II MHC restricted - CD8+ Tc cells is class I MHC restricted Role of Antigen-Presenting cells Processing of antigen is required for recognition by T cells Most cells can present antigen with class I MHC; presentation with class II MHC is restricyed to PACs - Display peptides associated with class II MHC to CD4+ TH cell : Antigen-presenting cells Display peptides associated with class I MHC to CD8+ Tc cells : Target cells Professional antigen-presenting cells : constitutively ecpress class II MHC, costimulatory molecules Nonprofessional antigen-presenting cells Evidence for different antigen-processing and presentation pathways Overview of cytosolic and endocytic pathways for processing antigen - Inhibitor of protein synthesis : emetine : Class I presentation inhibition - Endocytic processing blocker : chloroquine : Class II presentation inhibition Endogenous antigens : The Cytosolic Pathway Cytosolic proteolytic system for degradation of intracellular proteins - Immunoproteasome : induced by IFN-g, TNF-a, virus-infected cells TAP (transporter associated with antigen processing) Assembly and stabilization of class I MHC molecules Molecular chaperones : calnexin, calreticulin, tapasin Exogenous antigens : The Endocytic Pathway - Ii (CD74) : invariant chain - CLIP : class II-associated invariant chain peptide -HLA-DM : catalyze the exchange of CLIP with antigenic peptide - HLA-DO : negative regulator of class II antigen processing by binding to HLA-DM and inhibiting its role in the dissociation of CLIP from class II MHC molecule (b) HLA class II-peptide or CLIP Cross-Presentation of Exogenous Antigens Presentation of Nonpeptide Antigens - CD1 molecules : structurally related to MHC class I non-polymorphic - Group I : CD1a, CD1b, and CD1c - Group II : CD1d - Identified on cortical thymocytes: T-cell differentiation marker - Found on B cells and dendritic cells Antigen presentation by CD1 - CD1 molecules : structurally related to MHC class I non-polymorphic - Group I : CD1a, CD1b, and CD1c - Group II : CD1d - Identified on cortical thymocytes: T-cell differentiation marker - Found on B cells and dendritic cells CD1 is an MHC class I-like molecule which presents lipid antigens - CD1d의 구조분석: X-ray crystallography : deep electrostatically neutral antigen-binding groove : hydrophobic acyl groups of the lipids into the large hydrophobic pockets : polar groups (phosphate, carbohydrate) interact with the TCR : lipid antigen-specific T cells : NK-T cells : acidic endosomal compartments lipid antigens: partially unfolded at low pH -Group CD1 : present lipids from mycobacteria and Haemophilus influenzae stimulate CD4+, CD8+ T cells role in antimicrobial defense - CD1d : present lipids from parasites such as Plasmodium falciparum and Trypanosoma brucei