MHC and TCR

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Major Histocompatibility Complex (MHC) and T Cell
Receptors
M.Prasad Naidu MSc Medical Biochemistry, Ph.D.,Res
earch scholar
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Historical Background

• Genes in the MHC were first identified as being
  important genes in rejection of transplanted
  tissues
• Genes within the MHC were highly polymorphic
• Studies with inbred strains of mice showed that
  genes within the MHC were also involved in
  controlling both humoral and cell-mediated immune
  responses
• Responder/Non-responder strains

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Historical Background

• There were three kinds of molecules encoded by
  the MHC
• Class I
• Class II
• Class III
• Class I MHC molecules are found on all nucleated
  cells (not RBCs)
• Class II MHC molecules are found on APC
• Dendritic cells, Macrophages, B cells, other
  cells

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Historical Background
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Historical Background

• Class III MHC molecules
• Some complement components
• Transporter proteins

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Historical Background

• It was not until the discovery of how the TCR
  recognizes antigen that the role of MHC genes in
  immune responses was understood
• TCR recognizes antigenic peptides in association
  with MHC molecules
• T cells recognize portions of protein antigens
  that are bound non-covalently to MHC gene
  products
• Tc cells recognize peptides bound to class I MHC
  molecules
• Th cells recognize peptides bound to class II MHC
  molecules

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Historical Background

• Three dimensional structures of MHC molecules and
  the TCR have been determined by X-ray
  crystallography

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Structure of Class I MHC

• Two polypeptide chains, a long a chain and a
  short ß (ß2 microglobulin)
• Four regions
• Cytoplasmic region containing sites for
  phosporylation and binding to cytoskeletal
  elements
• Transmembrane region containing hydrophobic amino
  acids

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Structure of Class I MHC

• Four regions
• A highly conserved a3 domain to which CD8 binds
• A highly polymorphic peptide binding region
  formed from the a1 and a2 domains
• ?2-microglobulin helps stabilize the conformation

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Structure of Class I MHC

• Variability map of Class 1 MHC a Chain

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Structure of Class I MHCAg-Binding Groove

• Groove composed of an a helix on two opposite
  walls and eight ß-pleated sheets forming the
  floor
• Residues lining the groove are most polymorphic
• Groove accomodates peptides of 8-10 amino acids
  long

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Structure of Class I MHCAg Binding Groove

• Specific amino acids on peptide required for
  anchor site in groove
• Many peptides can bind
• Vaccine development

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Class I polymorphism
Locus Number of alleles (allotypes)
HLA - A 218
HLA - B 439
HLA - C 96
There are also HLA - E, HLA - F and HLA - G Relatively few alleles
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Structure of Class II MHC

• Two polypeptide chains,a and ß, of roughly equal
  length
• Four regions
• Cytoplasmic region containing sites for
  phosporylation and binding to cytoskeletal
  elements

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Structure of Class II MHC

• Four regions
• Transmembrane region containing hydrophobic amino
  acids
• A highly conserved a2 and a highly conserved ß2
  domains to which CD4 binds
• A highly polymorphic peptide binding region
  formed from the a1 and ß1 domains

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Structure of Class II MHC

• Variability map of Class2 MHC ß Chain

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Structure of Class I MHCAg-Binding Groove

• Groove composed of an a helix on two opposite
  walls and eight ß-pleated sheets forming the
  floor
• Both the a1 and ß1 domains make up the groove
• Residues lining the groove are most polymorphic

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Structure of Class I MHCAg-Binding Groove

• Groove is open and accomodates peptides of 13-25
  amino acids long, some of which are ouside of the
  groove
• Anchor site rules apply

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Class II polymorphism
Locus Number of alleles (allotypes)
HLA - DPA HLA - DPB 12 88
HLA - DQA HLA - DQB 17 42
HLA - DRA HLA - DRB1 HLA DRB3 HLA DRB4 HLA DRB5 2 269 30 7 12
There are also HLA - DM and HLA - DO Relatively few alleles
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Important Aspects of MHC

• 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 (considering only the
  major loci).
• 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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Important Aspects of MHC

• Because each MHC molecule can bind many different
  peptides, binding is termed degenerate.
• MHC polymorphism is determined only in the
  germline. There are no recombinational
  mechanisms for generating diversity.
• MHC molecules are membrane-bound recognition by
  T cells requires cell-cell contact.

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Important Aspects of MHC

• Alleles for MHC genes are co-dominant. Each MHC
  gene product is expressed on the cell surface of
  an individual nucleated cell.
• 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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Important Aspects of MHC

• Mature T cells must have a T cell receptor that
  recognizes the peptide associated with MHC. This
  is the second level of control.
• Cytokines (especially interferon-?) increase
  level of expression of MHC.

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Important Aspects of MHC

• Peptides from the cytosol associate with class I
  MHC and are recognized by Tc cells . Peptides
  from within vesicles associate with class II MHC
  and are recognized by Th cells.
• Why so much polymorphism?
• Survival of the species

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Structure of the T cell Receptor

• Heterodimer with one a and one ß chain of roughly
  equal length
• A short cytoplamic tail not capable of
  transducing an activation signal
• A transmembrane region with hydrophobic amino
  acids

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Structure of the T cell Receptor

• Both a and ß chains have a variable (V) and
  constant (C) region
• V regions of the a and ß chains contain
  hypervariable regions that determine the
  specificity for antigen

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Structure of the T cell Receptor

• Each T cell bears TCRs of only one specificity
  (allelic exclusion)

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Genetic Basis for Receptor Generation

• Generation of a vast array of BCRs is
  accomplished by recombination of various V, D and
  J gene segments encoded in the germline
• Generation of a vast array of TCRs is
  accomplished by similar mechanisms
• TCR ß chain genes have V, D and J gene segments
• TCR a chain genes have V and J gene segments

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Organization and Rearrangement of the T Cell
Receptor
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Comparison of TCR and BCR
Property BCR (sIg) TCR
Genes Genes Genes
Many VDJs, Few Cs Yes Yes
VDJ rearrangement Yes Yes
V regions generate Ag-binding site Yes Yes
Allelic exclusion Yes Yes
Somatic mutation Yes No
Proteins Proteins Proteins
Transmembrane form Yes Yes
Secreted form Yes No
Isotypes with different functions Yes No
Valence 2 1
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?d TCR

• Small population of T cells express a TCR that
  contain ? and d chains instead of a and ß chains
• The Gamma/Delta T cells predominate in the
  mucosal epithelia and have a repertoire biased
  toward certain bacterial and viral antigens
• Genes for the d chains have V, D and J gene
  segments ? chains have V and J gene segments
• Repertoire is limited

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?d TCR

• Gamma/Delta T cells can recognize antigen in an
  MHC-independent manner
• Gamma/Delta T cells play a role in responses to
  certain viral and bacerial pathogens

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TCR and CD3 Complex

• TCR is closely associated with a group of 5
  proteins collectively called the CD3 complex
• ? chain
• d chain
• 2 e chains
• 2 ? chains
• CD3 proteins are invariant

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Role of CD3 Complex

• CD3 complex necessary for cell surface expression
  of TCR during T cell development
• CD3 complex transduces signals to the interior of
  the cells following interaction of Ag with the TCR

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The Immunological Synapse

• The interaction between the TCR and MHC molecules
  are not strong
• Accessory molecules stabilize the interaction
• CD4/Class II MHC or CD8/Class I MHC
• CD2/LFA-3
• LFA-1/ICAM-1

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The Immunological Synapse

• Specificity for antigen resides solely in the TCR
• The accessory molecules are invariant
• Expression is increased in response to cytokines

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The Immunological Synapse

• Engagement of TCR and Ag/MHC is one signal needed
  for activation of T cells
• Second signal comes from costimulatory molecules
• CD28 on T cells interacting with B7-1 (CD80) or
  B7-2 (CD86)
• Others
• Costimulatory molecules are invariant
• Immunological synapse

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Costimulation is Necessary for T Cell Activation

• Engagement of TCR and Ag/MHC in the absence of
  costimulation can lead to anergy
• Engagement of costimulatory molecules in the
  absenece of TCR engagement results in no response
• Activation only occurs when both TCR and
  costimulatory molecules are engaged with their
  respective ligands
• Downregulation occurs if CTLA-4 interacts with B7
• CTLA-4 send inhibitory signal

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Key Steps in T cell Activation

• APC must process and present peptides to T cells
• T cells must receive a costimulatory signal
• Usually from CD28/B7
• Accessory adhesion molecules help to stabilize
  binding of T cell and APC
• CD4/MHC-class II or CD8/MHC class I
• LFA-1/ICAM-1
• CD2/LFA-3
• Signal from cell surface is transmitted to
  nucleus
• Second messengers
• Cytokines produced to help drive cell division
• IL-2 and others