Major Histocompatability Complexes

()Map\Tab IMMUNOLOGY (Map/Tab) ADAPTIVE IMMUNE SYSTEM LYMPHORETICULAR SYSTEM

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