Major Histocompatibility Complex and T Cell Receptor

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Major Histocompatibility Complex and T Cell
Receptor
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Major Histocompatibility Complex History

• Transplantation graft rejection
• Immune responses antibody formation
• Highly polymorphic
• Bind peptide recognized by T cells
• Three-dimensional structure determined by X-ray
  crystallography

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Structure of Class I MHC
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Structure of Class I MHC

• Two polypeptide chains, a long a chain and a
  short ß chain, called ß2 microglobulin
• Four regions
• Peptide-binding region - a groove formed from a1
  and a2 domains of the a chain
• 2. Immunoglobulin-like region highly
  conserved a3 domain - site to which CD8 on T
  cell binds

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Structure of Class I MHC(continued)

• Transmembrane region stretch of hydrophobic
  amino acids spanning membrane
• Cytoplasmic region contains sites for
  phosphorylation and binding to cytoskeletal
  elements

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Structure of Class I MHC
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Structure of Class I MHC Peptide-binding Region

• a groove composed of an a-helix on two opposite
  walls and eight ß-pleated sheets forming the
  floor
• residues lining groove most polymorphic
• peptide in groove 8-10 amino acids long
• specific amino acid on peptide required for
  anchor site in groove

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Variability For Polymorphism

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Structure of Class II MHC
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Structure of Class II MHC

• Two polypeptide chains, a and ß, of roughly equal
  length.
• Four regions
• Peptide-binding region a groove formed from the
  a1 and ß1 domains of the a and ß chains site of
  polymorphism
• Immunoglobulin-like region conserved a2 and ß2
  domains ß2 is site to which CD4 on T cell binds

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Structure of Class II MHC(continued)

• Transmembrane region stretch of hydrophobic
  amino acids spanning membrane
• Cytoplasmic region contains sites for
  phosphorylation and binding to cytoskeletal
  elements

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Structure of Class II MHC
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Variability For Polymorphism
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Peptide-binding grooves for class I and class II
MHC are structurally similar

• Both have a peptide-binding groove with a wall of
  two a helices and a floor of eight ß-pleated
  sheets
• Close-ended groove for class I MHC requires an
  8-10 amino acid-length peptide to bind
  open-ended groove for Class II MHC lets it bind a
  peptide 13-25 amino acids long, not all of which
  lie in the groove
• Anchor site rules apply to both classes

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Aspects of MHC

• MHC molecules are membrane-bound. Recognition by
  T cells requires cell-cell contact.
• Peptide from cytosol associates with class I MHC
  and is recognized by Tc cells. Peptide from
  vesicles associates with class II MHC and is
  recognized by Th cells.

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Aspects of MHC (continued)

• Although there is a high degree of polymorphism
  for a species, an individual has maximum of six
  different class I MHC products and only slightly
  more class II MHC products.
• A peptide must associate with a given MHC
  of that individual, otherwise no immune response
  can occur. That is one level of control.

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Aspects of MHC (continued)

• Mature T cells must have a T cell receptor that
  recognizes the peptide associated with MHC. This
  is the second level of control.
• Each MHC molecule has only one binding site. The
  different peptides a given MHC molecule can bind
  all bind to the same site, but only one at a time.

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Aspects of MHC (continued)

• MHC polymorphism is determined only in the
  germline. There are no recombinational
  mechanisms for generating diversity.
• Because each MHC molecule can bind many different
  peptides, binding is termed degenerate.
• Cytokines (especially interferon-?) increase
  level of expression of MHC.

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Aspects of MHC (continued)

• Alleles for MHC genes are co-dominant. Each MHC
  gene product is expressed on the cell surface of
  an individual nucleated cell.
• Why the high degree of polymorphism?

Survival of species!
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Structure of T Cell Receptor
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Structure of T Cell Receptor (TCR)

• Two polypeptide chains, a and ß, of roughly equal
  length
• Both chains consist of a variable (V) and a
  constant (C) region
• a chain V region has a joining (J) segment
• ß chain V region has both a J and diversity (D)
  segment

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Organization and rearrangement of the T cell
receptor
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Defects in TCR rearrangement
Defects in RAG genes leads to severe combined
immunodeficiency disease (SCID)
SCID patient infected with Candida albicans
Child with Omenn syndrome
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Structure of T Cell Receptor(continued)

• Hypervariable regions in V contribute to
  diversity of TCR
• TCR recognizes portions of MHC molecule and
  peptide bound in the groove
• Small population of T cells has a TCR comprised
  of ? and d chains ?d TCR specificity differs
  from aß TCR

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Structure of T Cell Receptor
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Properties of Ig and TCR Genes

• Ig
  TCR
• Many VDJs, few Cs yes
  yes
• VDJ rearrangement yes
  yes
• V-pairs form antigen yes
  yes recognition site
• Somatic hypermutation yes no

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Properties of Ig and TCR Proteins

• Ig
  TCR
• Transmembrane forms yes yes
• Secreted forms yes
  no
• Isotypes with different yes no
  functions
• Valency 2
  1

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CD3 Complex

• Group of four proteins associated with TCR
• Consists of a ?, a d, two e, and two ? chains
• All four proteins are invariant
• Functions 1) synthesized co-ordinately with TCR,
  required to bring TCR to surface
• 2) transduces activating signals to T cell
  when TCR recognizes MHC-peptide

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CD3 Complex With TCR
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Accessory Molecules Involved in Cell-Cell
Interactions

• T cell surface molecules that engage with
  ligand on 2nd cell when TCR recognizes
  MHC-peptide
• T Cell Ligand on 2nd
  Cell
• CD4 class II MHC (ß2
  domain)
• CD8 class I MHC (a3
  domain)
• LFA-2 LFA-3
• LFA-1 ICAM-1, ICA-2
  
• LFA Leukocyte Function-associated Antigen
• ICAM InterCellular Adhesion Molecule

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Accessory Molecules

• All are invariant
• Increase adhesion between two engaged cells
• Some show increased expression in response to
  cytokines

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Costimulatory Molecules

• Molecules on T cell and 2nd cell that engage to
  deliver 2nd signal required for activation of T
  cell
• Most important costimulatory molecules
• T cell Ligand on 2nd cell
• CD28 B7-1 (CD80), B7-2 (CD86)
  

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Interactions of Th Cell and APC
T helper lymphocyte
TCR
LFA-2
LFA-1
CD28
IL-1 IL-6 TNF-alpha IL-12 IL-15
TNF-beta IFN-gamma GM-CSF IL-4
CD4
Antigen- presenting cell
LFA-3
ICAM-1
Class II MHC
B7-1/B7-2 (CD80/CD86
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Interactions of Tc Cell and Target Cell
T cytotoxic lymphocyte
TCR
LFA-1
LFA-2
CD8
Target cell
Class I MHC
ICAM-1
LFA-3
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