Download (MHC) molecules

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, DPbless 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