Transcript MHC antigeny

MHC molecules, antigens
Prof. Ilona Hromadníková, PhD.
Antigens
• Exoantigens – external molecules recognised by
immune system (most frequently infectious
microorganisms)
• Autoantigens – antigens derived from own cells
• Superantigens – exoantigens, non-specific
stimulation of lymphocytes independently on
antigen specificity
• Allergens – in predisposed individuals induce
pathologic (allergic) immune response
Antigens - structure
Macromolecules or small molecules (haptens)
bound to carrier
• Soluble and/or expressed on the cell surface
• Proteins, glycoproteins, polysaccharides, lipids,
lipoproteins, nucleic acids, etc.
• Epitope – a part of antigen recognised by
immune receptors
• Immunocomplexes – complex of antigen with
antibody, which may bind complement
component
MHC class I GP
• expressed on all nucleated cells (no erythrocytes), various
expression on various cells
• bind antigenic peptides derived from self-proteins
(senescence, stressed, transformed and/or malignant cells),
viral peptides, bacterial peptides (intracellular parasites)
• presentation of antigenic cytosolic peptides to CD8+
cytotoxic T lymphocytes
• recognised also by NK cells, killer activatory receptors
(KAR – MICA, MICB, ULBP) and killer inhibitory
receptors (KIR- HLA-C, HLA-G)
Structure MHC class I GP
• 2 polypeptide chains:
Antigen binding site
α – chain: trans membrane, contains 3 globular
domains, encoded in MHC region
(chromosome 6) , non-covalent association with:
β2 – microglobulin (β2-m): non-polymorphic, encoded
outside MHC region (chromosome 15)
• α1 a α2 domains create a groove for endogenous
peptide (length: 8-10 amino acids). A groove is lined
by 2 α – helixes and its bottom consists of 8 antiparallel β chains. Antigen binding site is closed.
• peptide origin: product of normal and/or malignant
cell, viral peptide
Trans membrane
part
Anchor amino acids
MHC class I GP
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2 subgroups of MHC class I: Classic and Non-classic
Classic MHC class I - HLA-A, HLA-B a HLA-C locuses
HLA-A and HLA-B highly polymorphic (cca 750 alleles), HLA-C less polymorphic
Trophoblast (HLA-C, -E and –G expression). All HLA-C variants are recognised by killer
inhibitory receptors of NK cells, inhibition of NK cell cytotoxicity
Non-classic MHC class I - HLA-E, HLA-F and HLA-G locuses
less polymorphic, variable expression on different cells
HLA-G expression exclusively on placental trophoblast , inhibition of NK cell cytotoxicity,
immunotolerance against foetus
HLA-F molecules expressed on cells of various tissues
MIC, ULBP and CD1 molecules belong also under non-clasic MHC class I subgroup
– MIC (MHC-class I related chain – MICA, MICB) - low expression on epithelial cells.
Their expression increases with heat (other) stress together with the expression of
heat shock proteins (Hsp). MIC are recognised by killer activatory receptors of NK
cells.
– ULBP (UL-16 binding proteins) are recognised by killer activatory receptors of NK
cells.
– CD1 molecules encoded outside MHC region. CD1 molecules associate with β2-m,
they present to immune system (mainly to  T lymfo) non-protein antigens
(i.e. glycolipids)
Binding of peptides into MHC class I groove
• MHC molecules are transported during their synthesis into
endoplasmic reticulum (ER). In ER lumen proper folding of both
MHC class I chains, creation of antigen binding site for a peptide.
Proper folding of MHC class I molecule is enabled by association of
α –chain, β2-m and peptide.
• Cytosolic ubiquitinated proteins are cleaved by proteasome into
short peptides. Transport of peptides into ER via TAP1 and TAP2
proteins (Transporters Associated with Antigen Processing). TAP
proteins prefer transport of peptides containing 8-16 amino acides
with hydrophobic or basic amino acides on C-terminus.
• MHC molecule with peptide in antigen binding site is transported
from ER through Golgi apparatus on the cell surface
• MHC class I molecules are unstable without peptide in the groove
• After dissociation of peptides from MHC class I on the cell surface
MHC I class changes its confirmation, β2-m dissociates and α –
chain is internalized by the cell and fastly degraded
MHC class II GP
• Limited tissue distribution comparing with
ubiquitous MHC class I GP
• Usually expressed on antigen presenting cells
(APC) under normal conditions (monocytes,
macrophages, DC, B lymphocytes, Langerhans
cells of the skin, Kuppfer cells in the liver,
microglia in CNS)
• HLA-DR (highly polymorphic),DQ, DP locuses
• Presentation of exogenous peptides (ingested
microorganisms) to CD4+ T lymphocytes
Structure of MHC class II GP
• Heterodimers: one α-chain and one β-chain
• Both chains are glycoproteins, they have
external, linking, trans mebrane and
cytoplasmic parts
• Extracellular part is created by α1, α2, β1, β2
domains. α1 a β1 domains are variable, α2 a
β2 domains are constant.
• Non-covalent association of both chains,
synthetized separately, after synthesis
association with the third chain (γ); once the
complex is expressed on the cell membrane
γ–chain dissociates
• Presentation of exogenous antigens
(ingested by the cell), peptide length (15-35or more amino acids). Antigen binding site is
opened.
Antigen binding site
Binding of peptides into MHC class II groove
• Proteosynthesis of MHC class II GP in ER, association of
 and  chains, binding of invariant Ii chain into
antigen binding site (its blockage), transport of the
complex into Golgi apparatus, transport secretory
vesicle (MHC II + Ii)
• Phagocytosis or endocytosis of exogenous material by
APC, proteolytic cleavage into peptide fragments
(proteases), fusion of endosome with transport vesicle
derived from Golgi apparatus (MHC II + Ii): cleavage of
Ii chain into short peptide fragment CLIP (MHC+CLIP),
release of CLIP from the groove followed by exogenous
peptide binding (MHCII + exogenous peptide),
transport into the cell surface, presentation to CD4+ T
lymphocytes
Cross-presentation of antigen
• MHC class I molecules are able to present exogenous
peptides (cross-presentation)
• Material recognised by cell surface receptors
is endocyted, become a part of endosomes, where is
partially (but not completely) degraded and transported
into cytoplasm, where is cleaved by proteasomes,
peptides are transported into ER
• Another way, how extracellular peptides may be
presented on MHC class I molecules is fusion of late
phagosomes containing peptide fragments with ER
• The ability of cross-presentation differs between various
APC cells, the most efficient in DC
Major Histocompatibility Complex
• MHC (Major Histocompatibility Complex) in humans is called Human
Leukocyte Antigen (HLA), located on chromosome 6. MHC region is
polygenic (the existence of several MHC class I and II isotypes) and
polymorphic (the existence of a large number of various variants/alleles of
each gene).
• High polymorphism (10 – 100 alleles in certain locus, change of 1 or a few
amino acids, able to bind various antigens), most people are heterozygotes
for MHC proteins – paternally and maternally inherited alleles for certain
MHC isotype. Combination of MHC alleles on one chromosome is called
MHC (HLA) haplotype
• MHC gene expression is codominant – products of both alleles from the
same locus are in one cell expressed in the same quantity
• Certain MHC molecule (i.e. certain allele from HLA-A2 locus) is able to bind
peptides with similar structure – peptides share a binding motif xLeuxxxxxxLeu(Val)
Major Histocompatibility Complex
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high gene polymorfism
For transplant - histocompatibility between the donor and
the patient is crutial
HLA class I - A, B, C
HLA class II - DR, DQ, DP
Antigen presentation to T lymphocytes
• APC – phagocytosis of exogenous particle, creation of
phagosome, cleavage of proteins into peptides and
their presentation via MHC class II molecules to CD4+ T
lymphocytes
• T cells recognise both peptide in antigen binding site
and MHC class II molecule itself. This phenomenon is
called MHC restriction. TCR is specific for an unique
combination of peptide and MHC molecule.
TCR/CD3/CD4 – MHC II (extracellular peptide)
Costimulatory molecules:
(T lympho) LFA-1 – ICAM-1/-3 (APC)
(T lympho) CD28 – CD86/CD80 (APC)
Antigen presentation to T lymphocytes
Antigen presentation to T lymphocytes
• Th1 immune response- activation of
macrophages (eradication of intracellular
parasites)
• Th2 immune response- activation of B
lymphocytes (plasmatic cells, antibody
production, eradication of extracellular
parasites)
Antigen presentation to T lymphocytes
• Presentation of abnormal (damaged, stressed,
tumour), viral and other antigens to CD8+ T
(cytotoxic) lymphocytes via MHC class I
molecules
TCR/CD3/CD8 – MHC I (endogenous peptide)
Costimulatory molecules:
(T lympho) LFA-1 – ICAM (APC)
Activation of cytotoxic mechanisms (cell death),
dependent on Th1 lymphocytes
Apoptosis - cell death mediated by CTL
lymphocytes
Cytotoxic granules
(perforin, granzymes)
Infected cell