Immune Recognition : MHC and TCR interactions

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Immune Recognition MHC and TCR interactions
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Antigen Recognition

• B cells can recognise antigens via their surface
  Ig molecules
• T cells can only recognise antigen in association
  with a Major Histocompatibility Complex (MHC)
  molecule.

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T cells

• T cells display TCR as their antigen recognition
  protein
• When stimulated they become Cytotoxic or Helper T
  cells
• Secrete cytokines that recruit other cells of the
  IS
• TCRs only recognise short peptides.

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MHC T cells

• T cells have a requirement to recognise both the
  ANTIGEN and the MHC moleculeThis is because the
  molecular structure of the MHC-Antigen complex is
  arranged so that some of the polymorphic amino
  acids of the MHC molecule are in direct contact
  with the TCR
• Therefore T cell recognition of antigen is said
  to be MHC restricted.

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Antigen Processing and Presentation

• Fragmentation of protein into peptides
• Association of peptide with an MHC molecule
• Transport to cell surface for expression
• Different cellular pathways for association of
  peptide with MHC class I and class II molecules

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MHC Antigens

• MHC Class I
• present endogenously derived peptides.
• these can be either self or derived from viruses
• because MHC Class I is present on all cells any
  cell can interact with T cells if infected by a
  virus

• MHC Class II
• present exogenous antigen which has been
  phagocytosed and processed.eg. Bacteria
• This is performed by professional antigen
  presenting cells eg macrophages

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MHC

• MHC Class II
• seen only on the professional antigen processing
  cells e.g macrophage
• slightly less polymorphic
• accepts peptides of up to 15 aa acids

• MHC Class 1
• detected on all nucleated cells
• very highly polymorphic
• Tight fit for peptides of only about 9 aa
• consists of an a-chain of 3 domains associated
  with b-2 microglobulin

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MOLECULES OF T LYMPHOCYTE RECOGNITION

• Major histocompatibility complex (MHC)
  humanHuman Leukocyte Antigen (HLA) mouseH-2
• Gorer and Snell identified a genetic basis for
  graft rejection and Snell named it
  histocompatibility 2 (H-2). Nobel prize awarded
  to Snell.
• Highly polymorphic genes organized in a complex
  on chromosome 6 (human) and 17 (mouse).
• Glycoproteins expressed on the surface of cells.
  MHC class I is composed of one polypeptide,
  non-covalently associated with b2microglobulin.
  MHC class II is composed of two polypeptides,
  referred to as a and b.

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MHC Class I and Class II Proteins

• Class I
• Alpha Chain
• 3 External domains
• 1 Transmembrane
• 1 Cytoplasmic tail
• Encoded in MHC
• Beta-2 Microglobulin
• 1 External domain
• No transmembrane
• No Cytoplasmic tail
• Not encoded in MHC

• Class II
• Alpha Chain
• 2 External domains
• 1 Transmembrane
• 1 Cytoplasmic Tail
• Encoded in MHC
• Beta Chain
• 2 External domains
• 1 Transmembrane
• 1 Cytoplasmic Tail
• Encoded in MHC

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MHC Class I and Class II Proteins

• Class I
• Tissue Distribution
• All nucleated cells
• RBCs in some species
• Function
• Presentation of antigens to CD8 T cells

• Class II
• Tissue Distribution
• Antigen presenting cells
• Macrophages
• Dendritic cells
• B cells
• Thymic Epithelium
• Function
• Presentation of antigens to CD4 T cells

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MHC Class I and Class II Proteins
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STRUCTURE OF MHC MOLECULES AND PEPTIDES BOUND TO
THE GROOVE

• Crystal structure (solved in late 1980s)
  revealed a binding groove formed by anti-parallel
  b-pleated sheets (bottom of groove) and a-helices
  (sides of groove).
• a1 and a2 of MHC class I and a1 and b1 of MHC
  class II form mirror images of each other to
  create the peptide binding groove.
• Amino acids along the edges of the groove
  interact (through hydrogen bonds and ionic
  attractions) with the amino acids of the peptide
  to stabilize peptide binding (Figure).

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Peptides bind to MHC Class II molecules in a
common polyproline II conformation
Jardetzky et al., PNAS 93 734-738 (1996)
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MHC-I Structure
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Class IPeptide Binding
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Class IPeptide Binding
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MHC-II Structure
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Peptide Binding by Major Histocompatibility
Complex (MHC) Antigen-presenting Proteins
MHC I
MHC II

• Peptides of intracellular origin
• Peptides 9-10 residues long
• Deep pockets bind peptide sidechains
• Deep pockets bind peptide N- and C-termini

• Peptides of extracellular origin
• Peptides 15 residues or longer
• Shallow pockets bind peptide sidechains
• Peptide termini free
• H-bonds to peptide backbone

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MHC Polymorphism

• Both Class I and Class II genes are highly
  polymorphic
• Most polymorphic residues of Class I are in the
  alpha 1 and alpha 2 domains
• Most polymorphic residues of Class II are in the
  alpha 1 and beta 1 domains

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Location of Polymorphic Residues
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Location of Polymorphic Residues
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Allelic variation in MHC occurs at the peptide
binding site and on the top/sides of the binding
cleft
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What Does the aß T Cell Receptor (TCR) Recognize?

• Only fragments of proteins (peptides) associated
  with MHC molecules on surface of cells
• Helper T cells (Th) recognize peptide associated
  with MHC class II molecules
• Cytotoxic T cells (Tc) recognize peptide
  associated with MHC class I molecules

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Similar to BCR, the TCR alone cannot signal the T
cell that it has bound antigen The TCR is always
associated with CD3 (g,d,e) and z (zeta) chain.
These molecules are involved in signaling the T
cell when it engages antigen
The TCR plus CD3 is referred to as the TCR complex
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The TCR Complex

• TCR is expressed on the surface of T cells in
  noncovalent association with a complex of
  transmembrane polypeptides
• CD3 3 distinct polypeptide chains, g, d and e
• Members of the Ig superfamily
• The e chain associates with both g and d
• chaperone role in transporting newly
  synthesized TCR molecules to the cell surface
• Expressed exclusively on T cells
• Two identical z (zeta) chains
• 16 kDa
• Found on T cells, macrophages and NK cells
• Mice also can have a h (eta) form

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CD4 and CD8 Molecules

• Transmebrane molecules
• Referred to as co-receptor or accessory molecules
• Member of the Ig superfamily
• T cells are either
• CD4 ? CD4()CD8(-)
• CD8 ? CD4(-)CD8()

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CD4 and CD8 Functions

• Extracellular portion bind to the invariant
  portion of the MHC on the APC ? adhesion molecule
• MHC restriction
• CD4 ? binds Class II MHC
• CD8 ? binds Class I MHC
• Act as signal transducers
• Linked to specific kinases which are activated
  after binding of MHC peptide
• CD4 molecule binds HIV ? allowing for virus entry

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TCR-peptide-MHC complex
Peptide MHC binding is just like the binding of
drugs to other receptors.
Garcia, K.C. et al., (1998). Science 279,
1166-1172.
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TRI-MOLECULAR COMPLEXTCR-MHC-PEPTIDE
Hennecke and Wiley. 2001. Cell 1041-4
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van der Merwe and Davis. 2003. Annu Rev Immunol
21, 659-684
TCR binding to peptide-MHC
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peptide binding interface 21-34 proportion of
TCR contacts with the peptide26-47 contact are
different between TCR-MHC complex -the
contribution to the binding energy is still
uncleared!
Bandovich and Garcia. 2003. Immunity 18,7-11
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TRI-MOLECULAR COMPLEX CHARACTERISTICS
-CDR1 and CDR2 interact with MHC molecules (a
helices)
-CDR3 interacts with the peptide
-interaction always in the same orientation -45
to 70 degrees angle related to peptide -Va see
N-ter of the peptide -Vb see C-ter of the peptide
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TRI-MOLECULAR COMPLEX CHARACTERISTICS
- most of the binding interface is between the
TCR and MHC helices - conformational change
in the TCR CDR loops enhances TCR
crossreactivity - no conformational change in
the TCR constant region (except in one complex
out of ten)
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Binding properties of TCR-MHC-peptide interaction
van der Merwe and Davis. 2003. Annu Rev Immunol
21, 659-684
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PARADOX
-TCR-MHC interaction has a weak
affinity -affinity 10 mM -half-life 10s
-restricted numbers of ligands (100) are
displayed at the surface of antigen presenting
cells
-T cell activation requires a long interaction
with antigen presenting cells (2h)
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key-lock model
-binding via CDR1 and CDR2 -induces fitting of
the CDR3 loops on the peptide -stabilize
interaction
allows scanning of the antigen presenting cell
surface for efficient detection of foreign
peptides (rare and very similar to self-peptides)
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Antigen Recognition by Antibodies (Ab) and T-cell
Receptors (TCR)
Ab - Ag
TCR MHC/peptide

• Surface area 2x750 Å2
• Epitope discontinuous in antigen (Ag) sequence

• Surface area 2x1000 Å2
• Ag peptide contributes only 40 of surface area
• Epitope continuous in Ag sequence
• Otherwise similar to Ab - Ag recognition