Major histocompatibility complex MHC and T cell receptors

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Major histocompatibility complex (MHC) and T cell
receptors

• Jennifer Nyland, PhD
• Office Bldg1, Room B10
• Phone [phone]
• Email jnyland_at_uscmed.sc.edu

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Teaching objectives

• To give an overview of role of MHC in immune
  response
• To describe structure function of MHC
• To describe structure function of TCR
• To discuss the genetic basis for generation of
  diversity in TCR
• To describe the nature of immunological synapse
  and requirements for T cell activation

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Role of MHC in immune response

• TCR recognizes Ag presented in MHC
• Context is important
• Binding of Ag peptides in non-covalent
• Two types of MHC (class I and class II) are
  recognized by different subsets of T cells
• CTL recognizes Ag peptide in MHC class I
• T-helper recognizes Ag peptide in MHC class II

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Structure of MHC class I

• Two polypeptide chains
• Long a chain and short ß

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Structure of MHC class I

• Four regions
• Cytoplasmic contains sites for phosphorylation
  and binding to cytoskeleton
• Transmembrane contains hydrophobic AAs
• Highly conserved a3 domain binds CD8
• Highly polymorphic peptide binding region formed
  by a1 and a2

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Structure of MHC class I Ag-binding groove

• Groove composed of
• a helix on 2 opposite walls
• Eight ß sheets as floor
• Residues lining floor are most polymorphic
• Groove binds peptides 8-10 AA long

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Structure of MHC class I Ag-binding groove

• Specific amino acids on peptide are required for
  anchor site in the groove
• Many peptides can bind
• Interactions at N and C-terminus are critical and
  lock peptide in grove
• Center of peptide bulges out for presentation
• Consideration in vaccine development

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Structure of MHC class II

• Two polypeptide chains
• a and ß
• approx equal length

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Structure of MHC class II

• Four regions
• Cytoplasmic contains sites for phosphorylation
  and binding to cytoskeleton
• Transmembrane contains hydrophobic AAs
• Highly conserved a2 and ß2 domains binds CD4
• Highly polymorphic peptide binding region formed
  by a1 and ß1

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Structure of MHC class II Ag-binding groove

• Groove composed of
• a helix on 2 opposite walls
• Eight ß sheets as floor
• Both a1 and ß1 make up groove
• Residues lining floor are most polymorphic
• Groove binds peptides 13-25 AA long (some outside
  groove)

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Important aspects of MHC

• Individuals have a limited number of MHC alleles
  for each class
• High polymorphism in MHC for a species
• Alleles for MHC genes are co-dominant
• Each MHC gene product is expressed on surface of
  individual cell

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Important aspects of MHC

• Each MHC has ONE peptide binding site
• But each MHC can bind many different peptides
• Only one at a time
• Peptide binding is degenerate
• MHC polymorphism is determined in germline
• NO recombination mechanisms for creating
  diversity in MHC
• Peptide must bind with individuals MHC to induce
  immune response

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Important aspects of MHC

• How do peptides get into MHC groove?
• Class I peptides in cytosol associate with MHC
• Class II peptides from within vesicles associate
  with MHC

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Important aspects of MHC

• MHC molecules are membrane-bound
• Recognition by Ts requires cell-cell contact
• Mature Ts must have TCR that recognizes
  particular MHC
• Cytokines (especially IFN-?) increase expression
  of MHC

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T cell receptor (TCR)
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Role of TCR in immune response

• Surface molecule on Ts
• Recognize Ag presented in MHC context
• Similar to Immunoglobulin
• Two types of TCR
• a ß predominant in lymphoid tissues
• ? d enriched at mucosal surfaces

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Structure of the TCR (aß)

• Heterodimer
• a and ß chains
• approx equal length

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Structure of the TCR (aß)

• Regions
• Short cytoplasmic tail- cannot transduce
  activation signal
• Transmembrane with hydrophobic AAs
• Both a and ß have a variable (V) and constant (C)
  region
• V region is hypervariable, determines Ag
  specificity

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Important aspects of TCR

• Each T cell has TCR of only ONE specificity
• Allelic exclusion
• aß TCR recognizes Ag only in the context of
  cell-cell interaction and in correct MHC context
• ?d TCR recognizes Ag in MHC-independent manner
• Response to certain viral and bacterial Ag

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Genetic basis for receptor generation

• Accomplished by recombination of V, D and J gene
  segments
• TCR ß chain genes have V, D, and J
• TCR a chain genes have V and J

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TCR and CD3 complex

• TCR is closely associated with CD3 complex
• Group of 5 proteins
• Commonly called invariant chains of TCR
• Role of CD3 complex
• CD3 necessary for cell surface expression of TCR
• transduces signal after Ag interaction with TCR

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The immunological synapse

• TCR-MHC interaction is not strong
• Accessory molecules stabilize interaction
• CD4/MHC class II or CD8/MHC class I
• CD2/LFA-3
• LFA-1/ICAM-1

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The immunological synapse

• Specificity for Ag is solely in TCR
• Accessory molecules are invariant
• Cytokines change expression levels

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The immunological synapse

• Co-stimulation is also necessary for activation
  of T cells
• CD28/CD80 or CD86
• CTLA-4 on T cells can also ligate CD80/CD86
• Inhibitory signal
• downregulation

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Key steps in T cell activation

• APC must process and present peptides to Ts
• Ts must receive co-stimulatory signal
• Accessory adhesion molecules stabilize binding of
  TCR and MHC
• Signal from cell surface is transmitted to
  nucleus
• Cytokines produced help drive cell proliferation