Major Histocompatibility Complex (MHC) and T cell Receptor

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Major Histocompatibility Complex (MHC) and T
cell Receptor (TCR) Structure and Function

• Nicole D. Powell, Ph.D.
• powell.424_at_osu.edu
• September 6, 2006

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Lecture Objectives

• Basic Structure of MHC I and MHC II
• Basic Function of MHC I and MHC II
• Basic Structure of TCR complex
• Basic Function of TCR complex

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Immune System

• INNATE
• NONSPECIFIC
• CELLS INCLUDE
• EPITHELIAL BARRIERS, PHAGOCYTES, COMPLEMENT, NK
  CELLS

ADAPTIVE ANTIGEN (Ag) SPECIFIC CELLS INCLUDE T
CELLS, B CELLS
TWO TYPES OF Ag SPECIFIC RECEPTORS
B CELL RECEPTOR (Ig)
T CELL RECEPTOR (TCR)
RECOGNIZES SOLUBLE INTACT MACROMOLECULES
(proteins, lipids, polysaccharides) AND SMALL
CHEMICALS
ONLY RECOGNIZE PROCESSED Ag FRAGMENTS PRESENTED
BY MHC ON THE SURFACE OF ANTIGEN PRESENTING CELLS
(APCs)
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Antigen recognition during an adaptive immune
response

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CD8 T cells are MHC I restricted and recognize
cytosolic proteins CD4 T cells are MHC II
restricted and recognize extracellular and
intravesicular pathogens
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What is MHC Restriction?

• Allows individual T cells to recognize foreign Ag
  displayed on the surface of an individual APC
• Allows T cells to distinguish between self and
  non self
• In the thymus, the organ where T cells mature, T
  cells which
• do not recognize self-MHC molecules die (negative
  selection)
• Bind with low avidity to self peptide-MHC
  complexes survive and TCRs that bind with high
  avidity die (positive selection)
• Prevents destruction of self tissue
  (autoimmunity)

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What is MHC anyway??
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MHC basics

• MHC is essential for antigen presentation to T
  cells
• T cells constantly survey for foreign antigens
• Self MHC foreign Ag T cell response
• Self MHC self Ag No T cell response
• MHC is expressed or its expression can be
  induced on almost every nucleated cell in the
  body
• Viruses can infect virtually any nucleated cell
  so MHC I functions to alert the CD8 T cells
• MHC expression tells the immune system that the
  cell is a self cell
• MHC is a key factor in determining tissue
  matching for transplant donors and recipients

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• - Original function was linked only to graft
  rejection
• - Later found to be of critical importance to
  all immune responses involving protein antigens

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Properties of MHC genes

• Known as HLA in humans, H2 in mice
• MHC alleles are concomitantly expressed
• The set of MHC alleles on an individual
  chromosome is termed the MHC haplotype
• MHC genes are highly polymorphic
• Over 20 alleles in mice
• Hundreds of alleles in humans (most polymorphic
  genes in the human genome)
• Reason why it is difficult to find transplant
  donors, even among 1st degree relatives

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• Human MHC I and II Genes are located at separate,
  but nearby loci on the Chromosome 6
• The Class I locus contains three smaller loci of
  Genes for three distinct Class I Genes, named A,
  B and C.
• All code for Class I molecules, but each is
  distinct in its structure and binding capacity.
• Most people have two distinct variants of A, two
  of B and two of C, for a total of six distinct
  MHC I Genes.
• The Class I Gene codes only for the alpha protein
  of Class I beta-2 MicroGlobulin Gene is very
  constant and is located elsewhere in the Genome

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• The MHC II locus is split into three smaller loci
  named DP, DQ and DR.
• Most people have two variants of each, for a
  total of six MHC II Gene each coding for one
  alpha and one beta unit
• Since it is possible for an alpha unit from one
  Gene to associate with a beta of another, there
  are a maximum of twelve different MHC II
  molecules in a given individual.
• The prevalence of different HLA types vary widely
  in different populations
• Certain diseases occur in higher frequencies in
  individuals with certain MHC haplotypes.

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Examples of Significant Disease and HLA (MHC)
Association

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Psoriasis vulgaris
Dermatitis Herpetiformis (mouth mucosa)
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Characteristics of MHC-peptide interactions

• MHC molecules have a broad specificity for
  peptides, i.e. many different peptides can bind
  within the MHC binding cleft
• Peptides associated with MHC have a slow on and
  slow off rate
• MHC molecules do not discriminate from self and
  foreign peptides
• The MHC haplotype of an individual determines
  which peptides bind and how peptides bind

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MHC I structure

• Made up of 1 a chain and b2-microglobulin
• Polymorphic residues include the a1 and a2
  domains
• The a3 region binds T cell co-receptor CD8
• Peptide binding cleft accommodates peptides of
  8-11 residues
• Found on almost all nucleated cells

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MHC II structure

• Made up of 1 a chain and 1 b-chain
• Polymorphic residues include the a1 and b1
  domains
• The b2 region binds T cell co-receptor CD4
• Peptide binding cleft accommodates peptides of at
  least 10-30 residues
• Present only on professional APCs

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Professional APCs

• PROFESSIONAL APCs- Constitutively express
  high(er) levels of MHCII and costimulatory
  molecules and are efficient inducers of T cell
  responses
• Macrophage
• Efficient endocytosis/phagocytosis of antigen
• Express both MHC I and MHC II (although at lower
  levels than B cells and DCs)
• B cell
• Internalize Ag via Ig receptor (therefore
  restricted to single antigenic specificities)
• High constitutive levels of MHC II (highest of
  the three)
• Efficient activators of CD4 T cells
• Dendritic Cell (DC)
• Primary function is antigen presentation
• Efficient activators of naïve T cells
• High levels of MHC and costimulatory molecules
• Extensive folds and dendritic extensions allow
  for contact with multiple T cells

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T cell basics

• Central players in the adaptive immune response
• Unlike B cells, only recognize processed antigen
  presented by APCs in the context of MHC
• TCRs have a fine specificity for peptides
• CD4 helper T cells
• Activate macrophages to destroy phagocytosed
  microbes
• Stimulate the proliferation and differentiation
  of B cells
• MHC II restricted
• CD8 cytotoxic T cells
• Destroy cells infected with intracellular
  pathogens
• MHC I restricted

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Structure of the TCR

• TCR is a heterodimer linked by a disulfide bond
• Majority of TCRs composed of one a chain and one
  b chain
• Small subset is a g d heterodimer

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• Structure of the TCR
• Each a and b chain consists of one Ig like
  variable ( V ) domain and one Ig like constant (
  C ) domain
• The extracellular portion of the TCR is
  structurally similar to the Fab portion of the
  BCR/Ig molecule
• Like Ig, the V regions comprise the antigen
  binding sites of the TCR

Typical Antibody Molecule
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Structure of the TCR

• Extracellular domains linked to the plasma
  membrane by a transmembrane segment that has a
  short cytoplasmic tail
• The TCR is associated with CD3 and z proteins
  forming the TCR complex

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Structure of the TCR

• CD3 and z are non-covalently associated to the
  TCR
• Expression of the TCR, CD3 and z chain are
  required for antigen recognition and signalling
• TCR recognizes Ag
• CD3 and z signal

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So many antigens so few genes

• The human genome is presently estimated to
  contain 2025 thousand genes
• The number of TCRs recognizing different antigens
  is estimated at 2.5 x 107
• HOW IS IT POSSIBLE for
• 2.5 x 104 genes to encode
• 2.5 x 107 different TCRs????

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TCR diversity and somatic recombination

• alpha (a) and beta (b) or gamma (g) and delta (d)
  chains for TCRs are encoded by several different
  gene segments
• Gene segments are joined by somatic recombination
  to become a functional gene
• V segments (variable)
• D segments (diversity)
• J segments (joining)

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TCR VDJ
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• During lymphocyte development, receptor gene
  segments undergo somatic recombination to
  generate intact variable region exons to encode
  the variable region if each Ig and TCR chain.
• These events only occur in somatic cells,
  therefore the changes are not inherited

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V(D)J Joining

• Each gene segment (V, D, and J) has an adjacent
  Recombination Signal Sequence (RSS)
• These are recognized by two proteins encoded by
  two Recombination Activating Genes RAG-1 and
  RAG-2
• Defects in the RAG genes can cause SCID (severe
  combined immunodeficiency) due to the lack of
  expression of functional immune receptors (TCRs
  and BCRs)

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Clinical Problems associated w/ TCR and MHC

• Graft rejection
• MHC is different between donor and recipient T
  cells will destroy transplanted tissue

• Autoimmunity
• MHC presents self peptides and TCR recognizes
  them as foreign and destroys self tissue

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Graft Rejection
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Successful Graft
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Acute Graft Rejection
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Accelerated Graft Rejection
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Critical Questions

• Why is MHC important in health and disease?
• What can MHC tell us about an individuals
  response to antigen?
• What are some consequences of dysregulated TCRs?