Major Histocompatability Complexes

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Major Histocompatibility Complexes - B. Catchpole, RVC 2008

Introduction

T-cells rely on Major Histocompatability Complexes (MHC) to present antigen fragments for their recognition. MHC has evolved to form two classes for antigen presentation: MHC I presents digestion fragments from antigen in cellular cytoplasm, and MHC II presents digestion fragments from antigen in the tissue fluid. As such, MHC I tends to bind slightly smaller peptides (~9 amino acids) than MHC II (~15 amino acids).

Classes

MHC I

MHC I presentation pathway, courtesy of B. Catchpole, 2008

Structure

  • MHC class I is expressed on virtually all nucleated cells
  • MHC class I consists of a membrane-associated heavy chain bound non-covalently with a secreted light chain
    • Heavy chain:
      • Made up of three distinct extracellular protein domains
        • α1, α2 and α3
      • The C- terminus is cytoplasmic
    • Light chain:
      • Known as β2-microglobulin
      • Similar in structure to one of the heavy chain domains
      • Not membrane associated
        • But binds to the α3-domain of the heavy chain
Structure of MHC I molecule - Copyright Prof Dirk Werling DrMedVet PhD MRCVS
  • The MHC class I domains are structurally and genetically related to immunoglobulin and TcR domains
    • The outer domains (α1 and α2) are like the variable domains
    • The α3 domain and β2m are like thrconstant domains
  • MHC class I molecules are folded to form specific 3-dimensional structures
    • The α1 and α2 domains are folded to produce an antigen-binding groove
      • This groove can bind molecules of a limited size only (8-10 amino acids)
        • This limits the size of epitope seen by the T-cell receptors

Presentation Pathway

  • MHC I presents endogenous (that is, intracellular) peptides
  • Viral proteins are broken down to peptides by the proteasome and transferred to the endoplasmic reticulum via TAP (Transporters associated with Antigen Processing) molecules
  • In the ER peptides are processed with empty MHC I molecules and exported to the cell surface for presentation
  • MHC class I molecules present these to the T-cell receptors of CD8+ T-cells

MHC II

MHC II presentation, courtesy of Janeway, et al. 2008

Structure

  • MHC class II is expressed mainly on macrophages, dendritic cells and B-lymphocytes
  • MHC class II consists of membrane-associated α and β chains
    • Each chain is a transmembrane glycoprotein
    • The extracellular parts of each chain have two Ig-like domains
      • α1 and 7alpha;2, β1 and β2
        • The outer domains (α1 and β1) are variable-like
        • The inner domains (α2 and β2) are constant-like
  • The 3-dimensional structure of MHC class II is similar to MHC class I
    • The outer domains of the α and β chains fold in a similar way to the α1 and α2 domains of class I
      • Produce the antigen-binding groove
Structure of MHC II molecule - Copyright Prof Dirk Werling DrMedVet PhD MRCVS

Presentation Pathway

  • MHC II presents exogenous (that is, derived from the ECF) peptides
  • Endocytosed antigen interacts with MHC II in the cytoplasm to form a complex:
    • Antigen is endoycotsed from the ECF
    • Lysosomes fuse with primary endosomes to digest the antigen to peptides
    • MHC II is meanwhile being produced by the endoplasmic reticulum, along with an invariant chain chaperone
    • These pathways (endoytotic and secretory) merge to allow interaction between the antigen and MHC II:
      • The invariant chain is digested, leaving a CLIP peptide in the binding groove
      • Foreign antigen then replaces the CLIP peptide
  • The MHC II-antigen complex is then secreted to the cell surface for presentation to CD4+ T-cells

Interaction of MHC With Antigen

  • The MHC molecules do not recognise specific amino acid sequences of antigens
    • Instead, they recognise particular motifs of amino acids
  • The association of any MHC allele with a peptide may be determined by the presence of as few as two amino acids
    • However, these determinants must be present within a particular array
  • The actual identity of the amino acids in not important for MHC binding
    • Instead, the physical and chemical characteristics of the amino acid are vital
  • Interactions of individual amino acids at the head and tail of the peptide-binding groove control the binding of peptides
    • Are mainly positioned at the floor of the antigen-binding groove, or within the helices facing into the groove
    • These MHC amino acids associate with amino acids near the ends of the peptides
      • The intervening stretch of peptide folds into a helix within the groove
      • Is the target for T cell receptor recognition
  • MHC molecules have the capacity to bind to trillions of different peptides
    • Adopt a flexible floppy conformation until a peptide binds
    • Folds around the peptide to increase stability of the complex
    • Uses a small number of anchor residues to tether the peptide allowing different sequences between anchors and different lengths of peptides to bind

TCR-MHC Interaction

Molecules of T lymphocyte recognition - Copyright Prof Dirk Werling DrMedVet PhD MRCVS
  • Only peptide associated with self-MHC will interact with and activate T cells
    • T cells cannot be activated by a peptide on a foreign cell
    • T cells will react against foreign MHC molecules
      • This is the basis of graft rejection
Location of Polymorphic Residues - Copyright Prof Dirk Werling DrMedVet PhD MRCVS

The Genetics of the MHC (Polymorphism)

  • Each individual has 6 types of MHC
  • MHC molecules are co-dominantly expressed
  • The combination of alleles in a chromosome is called an MHC Haplotype
  • Different individuals have different critical amino acids within the MHC
    • I.e. different amino acids that determine peptide binding
    • This variation is termed MHC polymorphism
    • Each polymorphic variant is called an allele
  • Both type I and type II MHC molecules are highly polymorphic
    • Most polymorphic regions of class I are in the alpha 1 and alpha 2 domains
    • Most polymorphic regions of class II are in the alpha 1 and beta 1 domains
  • Most polymorphisms are point mutations
  • There are millions of variations in antibodies and TCR
    • However, with MHC there is very limited variation between molecules
  • Allelic variation within the MHC molecule occurs at the peptide binding site and on the top or sides of the binding cleft
  • Polymorphisms and polygenism in the MHC protects the population from pathogens evading the immune system
  • MHC polymorphism has been best studied in the human
Location of Polymorphic Residues - Copyright Prof Dirk Werling DrMedVet PhD MRCVS

In the Human

  • Humans express:
    • Three types (loci) of MHC class I molecules
      • HLA (Human Leukocyte Antigen)- A, B, and C
    • Three loci of MHC class II molecules
      • HLA-DP, DQ and DR
  • In the entire human population there are only approximately 50 different variants (alleles) at each MHC class I and class II locus
    • The variation within MHC class I is entirely on the class I heavy chain
      • The β2m is invariant
    • The variation within MHC class II is mainly within the β chains
  • Every individual has two alleles at each MHC locus
    • One inherited from each parent
    • Any individual will therfore express two variants at most at each locus
      • This gives a maximum variability for an individual of:
        • 6 different variants of MHC class I
          • 2 each of HLA- A, B and C
        • 6 different variants of MHC class II
          • 2 each of HLA- DP, DQ and DR
  • Many animal species have fewer loci than the human
    • E.g. ruminants have no MHC class II DP

MHC and Disease

  • Antigen from a pathogen has to be seen by the host MHC before an efficient immune response can occur
    • There is therefore a constant evolutionary battle between the host and the pathogen
      • There is selective pressure on the pathogen to evolve proteins that do not interact with the host MHC
      • There is selective pressure on the host to continue to recognize the pathogen
  • The consequence of this parallel evolution is that host-pathogen relationships can lead to the selection of particular MHC variants, for example:
    • MHC class II alleles DR13/DR1*1301 are prevalent in Central and Western Africa
      • Impart resistance to malaria
    • MHC-DRB1 is prevalent in Western Europe, but rare in the Inuit populations of North America
      • Associated with the clearance of hepatitis B infection in Western Europe
      • Inuits have the highest incidence of hepatitis B in the world
    • In humans there are also strong associations between certain alleles and some autoimmune diseases, for example:
      • Diabetes mellitus
      • Ankylosing spondylitis
      • Rheumatoid arthritis
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