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Major Histocompatibility Complex II Structure and Functions

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Major Histocompatibility Complex II (MHC II molecules)

  • Only select immune cells, including DCs, active macrophages, mature B cells, and some innate lymphocyte cells, produce Class II MHC molecules (ILCs).
  • Class II molecules on DCs and B cells are essential for launching an adaptive immune response, as we will see. Class II MHC molecules, like class I MHC proteins, are transmembrane proteins with two different chains.
  • However, MHC class II molecules fold to produce a three-dimensional antigen-binding pocket where only non-self peptide fragments can be presented to other immune cells.
  • MHC class II molecules differ from MHC class I in that they feature a groove that is far deeper, allowing a longer peptide produced from a foreign material to bind.
  • MHC I molecules have binding pockets that are capable of anchoring both self and non-self peptides, whereas MHC II molecules bind to bigger, non-self peptides.
  • Non-self peptide antigen pieces must be present in the MHC groove in order for T cells, which activate other immune cells, to be activated. Antigen processing is the process by which peptides bind to MHC molecules prior to their transfer to the surface of the host cell.
Major Histocompatibility Complex II
Major Histocompatibility Complex II

Cellular Distribution of Major Histocompatibility Complex II (MHC II molecules)

  • In contrast to class I MHC molecules, class II molecules are expressed constitutively only by antigen-presenting cells, primarily macrophages, dendritic cells, and B cells; however, thymic epithelial cells and other cell types can be induced to express class II molecules and to function as antigen-presenting cells under certain conditions and in response to stimulation by certain cytokines.
  • Among the numerous cell types that express class II MHC molecules, there have been reported to be significant expression discrepancies. In some instances, class II expression is dependent on the stage of cell development.
  • Class II molecules, for instance, cannot be found on pre-B cells but are constitutively produced on the membrane of mature B cells.
  • Until they are triggered by contact with an antigen, monocytes and macrophages express only modest quantities of class II molecules.
  • Due to the fact that each of the classical class II MHC molecules consists of two distinct polypeptide chains that are encoded by different loci, a heterozygous individual expresses not only the parental class II molecules, but also molecules including α and  β chains from different chromosomes.
  • For instance, an H-2k mouse expresses class II IAk and IEk molecules; an H-2d mice expresses class II IAd and IEd molecules. Four parental class II molecules and four molecules containing one parent’s  α chain and the other parent’s β chain are expressed in the F1 offspring produced by mating mice with these two haplotypes.
  • Since the human MHC contains three classical class II genes (DP, DQ, and DR), an individual who is heterozygous expresses six parental class II molecules and six molecules containing α and  β chain combinations from any parent.
  • The existence of numerous -chain genes in mice and humans, and multiple β-chain genes in humans, increases the number of various class II molecules expressed by one individual.
  • This diversity likely increases the amount of antigenic peptides that can be presented, which is helpful for the organism.

Structure of Major Histocompatibility Complex II (MHC II molecules)

As stated previously, MHC class II molecules are nearly exclusively located on APCs. The peptides bound by MHC class II are produced from the breakdown of proteins that have entered the cell from the outside via phagocytosis or receptor-mediated endocytosis. Because APCs also catch and digest exhausted host proteins, the vast majority of peptides presented on MHC class II molecules are “self” and do not activate CD4+ T cells because the formation of central tolerance has eliminated these specificities from the Th cell repertoire. When an APC presents a non-self peptide coupled to MHC class II, a Th response is produced.

a. MHC Class II Component Polypeptides

  • The α and β chains of MHC class II proteins are glycoproteins of comparable size and structure in both humans and mice (24–32 and 29–31 kDa, respectively).
  • Both chains possess an N-terminal extracellular domain, an Ig-like extracellular domain, a hydrophobic transmembrane region, and a short cytoplasmic tail.
  • The N-terminal α1 and β1 domains of the α and β chains, respectively, comprise the peptide-binding area.
  • The α2 and β2 domains are homologous to the Ig fold but play no role in peptide binding.
Structure of the MHC Class II Protein
Structure of the MHC Class II Protein

b. MHC Class II Peptide-Binding Site

  • The peptide-binding groove of MHC class II molecules is structurally similar to that of MHC class I molecules.
  • However, the extremities of the MHC class II groove are wide open, allowing for the binding of significantly longer peptides (up to 30 amino acids).
  • However, the bulk of peptides discovered in MHC class II grooves range in length from 13 to 18 amino acids.
  • The open ends of the MHC class II groove also imply that binding does not rely on conserved anchor residues at the ends of peptides, but is instead mediated by hydrogen bonds between the peptide backbone and the sidechains of specific MHC amino acids.
  • Researchers have discovered that antigenic peptides that successfully bind to the floor of the MHC class II groove have a particular conserved secondary structure (resembling a polyproline chain) in the portion of the peptide that aligns with critical acidic MHC residues located in the groove’s centre.
  • Due to this conformational requirement, MHC class II proteins typically bind a more limited array of proteins than MHC class I proteins.
Peptide in MHC Class II Binding Groove
Peptide in MHC Class II Binding Groove

How are self and non-self peptides deposited in the MHC II binding pocket?

  • Class II MHC molecules are distinct from class I MHC molecules in that they bind antigen pieces that originate from outside the cell, undergoing exogenous antigen processing.
  • MHC class II molecules can only bind to foreign particles (e.g., bacteria, viruses, poisons) that have been taken up by endo- or phagocytosis. Antigen-presenting cells (APCs) are immune cells that attach non-self antigen to MHC class II molecules. These cells include macrophages, DCs, and B cells.
  • Processing of exogenous antigen by macrophages and DCs begins with phagocytosis of the intruder. Instead of phagocytosing, B cells have receptors that bind pathogens or other antigenic substances (e.g., sloughed fragments of microbial cell wall).
  • Once antigen has bonded to B-cell receptors, receptor-mediated endocytosis transports the antigen-receptor complex inside the cell.
  • In every instance, breakdown in the phagolysosome or autolysosome releases antigenic peptides belonging to the invader. Combining with preexisting class II MHC molecules, these peptides are transported to the cell surface.
  • As with class I MHCs, only peptides that fit snugly into the binding pocket of class II MHCs are bound. This peptide is now capable of being identified by CD4+ T-helper cells.
  • DCs are especially proficient at presenting foreign peptides to T cells and activating them to become T cells.
  • CD4+ T cells do not directly kill target cells, unlike CD8+ T cells. They instead release cytokines to coordinate an integrated innate and adaptive immune response.
Major Histocompatibility Complex II (MHC II molecules)
Major Histocompatibility Complex II (MHC II molecules)

Functions of Major Histocompatibility Complex II (MHC II molecules)

  • By choosing the mature CD4+ T cell repertoire in the thymus and activating these lymphocytes in the periphery, the TCR–peptide: MHC class II interaction is essential for the induction and control of adaptive immunity.
  • The given peptide’s tight attachment to the MHC molecule ensures stable peptide binding, which enhances T cell recognition of the antigen, T cell recruitment, and an effective immune response.
  • MHC class II molecules are crucial for the commencement of the antigen-specific immune response because they sample and present antigens from external sources.


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