MHC Classes and Immune Response

• Humoral and cell-mediated responses are triggered in a vertebrate body by foreign agents or proteins called antigens
• In a humoral response B lymphocytes or B cells interact with antigens, and antigen-selected antibody-secreting B cells create antibodies that eliminate the antigen
• In a cell-mediated response T lymphocytes or T cells interact with antigens via T-cell receptors, leading to cytokine secretion and the killing of infected cells by antigen-selected T cells

Three Major MHC Classes

• Class I MHC genes encode glycoproteins expressed on all nucleated cells and interact with Tc (CD8+ T) cells
• Class II MHC genes encode glycoproteins expressed on APC cells and interact with TH (CD4+ T) cells
• Class III MHC genes encode secreted proteins like complement and tumor necrosis factor (TNF)

Structure and Function of MHC Molecules

• Class I molecules are members of the Ig superfamily
• It includes a larger 45 kDa glycoprotein a chain and a smaller 12 kDa ẞ2-microglobulin protein
• Class II molecules are members of the Ig superfamily
• They are heterodimeric with a 33 kDa a chain and a 28 kDa ẞ chain, both of which pass through the plasma membrane
• A peptide-binding cleft is formed by the pairing of the a1 and ẞ1 domains

Polymorphism

• Polymorphism occurs when two or more clearly different phenotypes exist in the same population of a species
• Class I and II molecules exhibit polymorphism in the peptide-binding region with several hundred different allelic variants in humans
• Up to six class I and 12 class II molecules are expressed per person
• A given MHC molecule can bind numerous different peptides, and peptides can bind to several different MHC molecules
• In Class I MHC-peptide interactions Present peptides to CD8+ T cells
• Some amino acids anchor the peptide into the groove, and other amino acids are available to interact with a TCR
• Class II MHC-peptide interactions Present antigen peptides to CD4+ T cells
• They exhibit anchor amino acid residues that lock peptides into the groove and extend other amino acid residues from the groove to interact with TCRs

Peptide Size and Structure

• Class I molecules have a closed peptide-binding groove, binding 8-10 amino acids with anchor residues at both ends of the peptide, generally hydrophobic carboxyl-terminal anchor
• Possesses an extended structure in which both ends interact with the MHC groove but middle arches up away from the MHC molecule
• Class II molecules have an open peptide-binding groove, binding 13-18 amino acids with conserved residues distributed along the length of the peptide;
• Possesses an extended structure that is held at a constant elevation above the floor of the MHC groove

General Organization and Inheritance of MHC

• The MHC locus encodes three major classes of molecules
• The Class I gene contains a 5' leader exon for a signal peptide followed by 5-6 exons encoding the alpha chain
• The signal peptide is eventually removed
• Allele is one of a number of alternative forms of the same gene or same genetic locus (a group of genes)
• Haplotype is each set of allele
• Inbreeding is reproduction from the mating of parents who are closely related genetically
• Each individual inherits one haplotype from each parent
• Inbreeding of mice has allowed for more standardized MHC genotypes to control variability
• Homozygous having the same alleles at a particular gene locus on homologous chromosomes
• Heterozygous having different alleles at one or more corresponding chromosomal loci
• MHC alleles are codominantly expressed, meaning both maternal and paternal MHC genes are expressed in offspring cells
• This gives the best chance for an organism to present all possible antigen peptides and can make transplantation difficult since humans are heterozygous at each locus
• Class I/II molecules exhibit diversity at individual AND species levels
• Individuals express MHC alleles inherited from both parents and alleles also differ between individuals, creating enormous diversity, and flexibility in responding to environmental changes

Role of the MHC and Expression Patterns

• MHC molecules present both intracellular and extracellular antigens
• Class I presents intracellular antigen peptides, including self-peptides, which provides a way for "checking" that cells are self and healthy
• Can also be used to show which cells have been infected with viruses or are abnormal.
• Class II presents extracellular antigen peptides found on cells involved in immune responses, usually APCs
• MHC class I expression is found throughout the body on all nucleated cells
• MHC class II is primarily restricted to antigen-presenting cells
• If cells constitutively express MHC Class II, makes them “professional” APCs
• MHC expression can change with changing conditions because of Genetic regulatory components, Viral Interference and Cytokine-mediated signaling
• Class II MHC alleles play a critical role in immune responsiveness, with different capability to present antigens dictating the overall strength of response from individual to individual and T cells
• T cells are restricted to recognizing peptides presented in the context of self MHC alleles
• CD8+/CD4+ T cells can only recognize peptides presented by MHC class I/II, respectively and the presenting cell's MHC haplotype must match the T cell's haplotype
• Only processed antigen peptide fragments can be recognized
• Evidence suggests different antigen processing and presentation pathways

Endogenous and Exogenous Processing

• Class I presentation requires cytosolic or endogenous processing
• Class II presentation requires exogenous processing
• In the endogenous pathway of antigen processing, peptides are generated by proteasome protease complexes and Ubiquitin proteins, used to “tag” intracellular proteins for degradation, are fed into proteasomes
• These peptides are transported by Transporter associated with antigen processing (TAP) molecules from the cytosol to the rough endoplasmic reticulum (RER)
• MHC class I molecules synthesized on ribosomes on the RER anchor in the RER membrane following their translation with help from chaperone proteins
• In the exogenous pathway of antigen processing, peptides are generated from internalized antigens in endocytic vesicles, taken in within endosomes
• Simultaneously, MHC class II molecules are produced and exported from the ER in vesicles
• Invariant chain (li, CD74) prevents peptides from binding to the groove too early in the ER and guides transport of class II MHC molecules to endocytic vesicles, and uses sorting signals in cytoplasmic tail
• Li is initially degraded by proteolytic activity within endocytic compartments to class II-associated invariant chain (CLIP) and HLA-DM exchanges CLIP out of the groove for a peptide fragment

Cross-presentation

• Dendritic cells appear to be the primary cross-presenting cell type, where exogenous antigens are redirected to the endogenous presentation pathway
• Allows the presentation on MHC class I molecules, priming CD8+ T-cell responses, and dendritic cells are the only APCs (so far) to exhibit this activity in vivo
• If DC can present foreign antigen to CD4+ helper T cell, it gets “license” to redirect exogenous Ag into the endogenous pathway to initiate the correct response
• "License" might be back/forth cytokine signal between the APC and helper T cell, a situation right for cross-presentation
• Some nonprotein Ag can be recognized by T cells and presentation is not via classic MHC molecules
• The CD1 family of nonclassical class I molecules can present lipids