By Levi Clancy for Student Reader on
The major histocompatibility complex (MHC, or MHC complex) is present in all vertebrates, and is encoded by a group of genes called HLA in humans and H-2 in mice.
Products of these genes are mostly cell surface glycoproteins involved in antigen presentation. MHC molecules must be bound to a peptide (it does not even have to be pathogenic) in order to be brought to the cell surface by the endoplasmic reticulum. The peptide-binding residues within the MHC determine what kinds of peptides it can bind.
While B cells interact with free antigens, T cells interact only with antigens that are associated with a major histocompatibility complex, thus limiting T cells to interaction with antigens at cell surfaces.
|Class I MHC genes||Class I MHC genes encode a glycoprotein that presents fragments of peptides synthesized inside the cell. If the peptide is foreign, then the cell is killed by CD8 (cytotoxic) T cells; this mechanism is useful for eliminating virally infected cells. Class I MHC molecules encoded by the human A, B & C loci (or murine K & D loci) are classical Class I MHC molecules; other Class I genes encode non-classical Class I MHC molecules. Classical Class I MHC molecules are expressed in almost every cell type, while non-classical Class I MHC molecules are more cell-specific and are expressed in very few cell types.|
|Class II MHC genes||Class II MHC genes encode a glycoprotein expressed primarily by macrophages, dendritic cells, B cells and T cells (all of which are proliferating antigen presenting cells). This glycoprotein presents fragments of peptides floating in the environment to CD4 (helper) T cells. If the peptide is foreign, then the CD4 cell is activated and goes on to help B cells and participate in inflammation. The chains of this glycoprotein are encoded by the DR, DQ and DP gene (IA and IE in mice). Please remember that 'D' refers to murine Class I MHC genes, while DR, DQ and DP refer to human Class II MHC genes. As with Class I, there are other Class II MHC genes (not mentioned) genes which are cell-specific and highly specialized.|
|Class III MHC genes||Mostly encode secreted proteins with immunological functions, including inflammation and complement. Class I and Class II MHC genes are structurally similar and flank the Class II loci. Class III MHC genes encode C4, C2 and Factor B (all involved in the complement cascade) as well as inflammatory cytokines (including tumor necrosis factor (TNF)).|
Class I major histocompatibility complex
Class I MHC molecules bind peptides and present them to cytotoxic T cells. A mammalian cell can express all Class I MHC alleles (up to six) at a time. Class I MHC molecules contain a 45kD transmembrane glyocoprotein α chain associated noncovalently with a 12kD β2-microglobulin. The three Class I MHC genes -- A, B and C in humans; K, D and L in mice -- are polymorphic and each encode a different α chain (although be clear that each chain contains α1, α2 and α3 subunits). α chains contain α1, α2 and α3 domains; the α3 region contains a cytoplasmic tail that goes through the lipid bilayer and into the cytoplasm. To summarize, the Class I region of HLA contains HLA-A, HLA-B and HLA-C, which each encode different α chains. Lastly, the noncovalently bound β-2 microglobulin is not encoded within the MHC, but is critical for getting the MHC protein to the cell surface.
Between the α1 and α2 regions is the peptide binding groove (aka antigen binding groove), which presents antigenic peptides to CD8 (cytotoxic) T cells. Antigenic peptides -- usually about nine amino acids -- anchor into the groove at both ends via hydrogen bonds; without this anchoring, the Class I MHC glycoprotein is not brought to the cell surface. Longer peptides bulge out in the middle, while shorter peptides are taught. The middle of the peptide makes negligible contact with the MHC molecule, and is instead available for direct T cell receptor contact.
In the absence of β2-microglobulin, Class I MHC molecules are not expressed on the cell surface. A cell that does not express β2-microglobulin will have Class I MHC molecules floating in the cytoplasm but completely absent from the cell surface; if these same cells are transfected with a functional β2-microglobulin gene, then they begin to express Class I MHC molecules on their cell surface. The enzyme papain cleaves Class I MHC molecules near the transmembrane domain, thus releasing just the extracellular portion (α1, α2, α3 and β2-microglobulin).
Class II major histocompatibility complex
Class II MHC molecules bind peptides and present them to helper T cells. Encoded by the centromeric end of HLA, the Class II MHC protein is (under normal conditions) found on macrophages, dendritic cells, B cells and activated T cells; however, in inflamed tissue, other cells can also express Class II MHC proteins. Class II MHC genes encode 32kD α and 27kD β transmembrane chains, and an intracellular invariant and non-polymorphic Ii chain. The α chain consists of α1 and α2 domains; the β chain consists of β1 and β2 domains. Just as with Class I MHC molecules, the α chain and β chain are noncovalently bound transmembrane glycoproteins with a cytoplasmic anchor.
Between the α1 and β1 domains is the peptide-binding cleft. Just as with the Class I cleft, the Class II cleft presents a peptide antigen; however, the Class II cleft binds antigens of at least 13 peptides (sometimes much longer) that are held in place along their backbone (instead of anchored at the ends) by interactions between cleft residues and the amino acids of the antigen. CD4 (helper) T cells recognize antigens presented by the Class II MHC protein.
The Class II region of HLA contains three genes (HLA-DR, HLA-DP and HLA-DQ) which each encode multiple different α and β chains. This allows a single translation of the HLA Class II genes to produce multiple different Class II MHC complexes. HLA-DR encodes three β chains and a single α chain; HLA-DP encodes one each of β1, β2, α1 and α2; HLA-DQ encodes one each of β1, β2, β3, α1 and α2. Please note, however, that α and β chains from different genes never mix; individual MHCs are always all HLA-DP, HLA-DR or HLA-DQ. Also, mice carry just two Class II Genes (IA, or AαAβ, and IE, or EαEβ).
Cell-surface peptide-bound MHCs bind to T Cell Receptors (TCRs). TCRs have a combining site which interacts the the α helices of α1 and α2, as well as the bound peptide. The center of the MHC-bound peptide nestles into a hydrophobic pocket between the CDR3α and CDR3β regions of the TCR. CDRs 1 and 2 of the Vα domain interact with the NH2-terminus of the MHC-bound peptide; CDR2 1 and 2 of the Vβ domain interact with the C-terminus of the MHC-bound peptide, as well as some of the MHC helices.
Peptide binding cleft
The binding of a peptide to an MHC molecule is very stable under physiologic conditions. Thus, most MHC molecules on a cell surface are associated with a peptide. Each cell expresses ∼105 copies of each Class I molecule, with 2,000 different peptides being presented 100 to 4,000 times on each cell.
|Class I MHC||Class II MHC|
|Peptide binding cleft||Between α1 and α2, and closed at both ends.||Between α1 and β1, and open at both ends.|
|Bound peptide structure||8 to 10 amino acids, with hydrophobic anchors at each end that interact with the MHC molecule and a middle that interacts with the T cell receptor.||13 to 18 amino acids, with residues along its length that interact with MHC molecules (no anchors). The T cell receptor interacts along the entire length of the peptide.|
|Bound peptide info||Usually an endogenous cellular protein that was digested in the cytosol and then migrated to the cisternae of the endoplasmic reticulum. Contains specific residues for binding to a particular MHC molecule.||Usually an exogenous protein that is derived from cells that have been phagocytosed or endocytosed. As with Class I MHC molecules, may bind self or non-self proteins (the T cell receptor distinguishes self from non-self).|
There are three different Class I MHC molecules -- A, B and C in humans; K, D and L in mice -- which each bind a different kind of peptide; within each gene, each allele delivers more specificity. Class I MHC molecules usually bind hydrophobic nonameric (nine amino acid) peptides, with specificity defined by same or similar amino acids at certain positions. Different alleles encode different peptide binding cleft residues at these positions.
Class II MHC molecules bind longer peptides than Class I MHC molecules, but only the central 13 amino acids actually interact with the molecule. These central 13 amino acids are conserved, meaning that certain patterns will specifically bind to certain Class II MHC molecule alleles. Peptides binding to Class I MHC molecules are bound primarily at their ends, while peptides binding to Class II MHC molecules are hydrogen-bound along their core amino acids (as opposed to being anchored at their ends).
Class I and Class II MHC genes -- present on Chromosome 6 in humans (Chromosome 17 in mice) -- are polygenic, polymorphic and codominant. Polygenic DNA encodes multiple proteins with similar structure and function. A polymorphic gene has many different alleles which are all common within a population. Codominance means that both alleles of a gene -- the maternal and the paternal copy -- are equally expressed.
Antibodies and T Cell Receptors (TCRs) use mutation, recombination and other techniques to generate diversity. However, MHC Class I and II molecules just use promiscuity to bind the vast population of peptides. Class I and Class II molecules have low specificity, allowing a single molecule to bind many different kinds of peptide. In addition, Class I and Class II genes are highly polymorphic; for some genes there are over 100 common alleles. Within these alleles, the region encoding the peptide binding cleft has the highest variability.
With so many alleles, most individuals are heterozygous for MHC Class I and MHC Class II genes. However, inbred populations sometimes are homozygous for alleles that encode MHCs able to bind no protein. Although rare, this condition drives home the point that MHC diversity is at the population level, not the individual level (unlike with antibodies and TCRs, whose diversity is generated during hematopoiesis).
Class I genes are expressed co-dominantly. This means that all six alleles (three on each chromosome) are expressed together. As a result, a single cell can have up to six different types of Class I MHCs on its surface. Class II genes are expressed only on proliferating antigen-presenting cells (macrophages, dendritic cells, B cells and activated T cells. Because each class II molecule consists of two proteins encoded by two genes, an individual not only has combinations of individual α and β alleles, but also hybrid Class II MHCs contain maternal and paternal α and β chains (heterozygote complementation).
The major histocompatibility complex is encoded by HLA genes in humans and H-2 genes in mice.
HLA and H-2 genes encoding the MHC itself are classical MHC genes; HLA and H-2 genes which do not encode the MHC are non-classical MHC genes). Non-classical genes are described in the table below, with non-classical genes without important immune functions are marked with a degree symbol.
Although most non-classical genes have mysterious functions, it is suspected that some have MHC-like function.
H-2 genes (the murine MHC-encoding genes)
|MHC Class||I||II||Class III||I|
|Gene products||H-2K||IAαβ||IEαβ||Complement||TNF-α & TNF-β||H-2D||H-2L|
HLA genes (the human MHC-encoding genes)
|MHC Class||II||Class III||I|
|Region||DP||DQ||DR||C4, C2 and BF||B||C||A|
|Gene products||DPαβ||DQαβ||DRαβ||Complement||TNF-α & TNF-β||HLA-B||HLA-C||HLA-A|
|Non-Classical Gene||MHC Class||Product|
|C2, C4a, C4b, Factor B||Class III||Complement proteins.|
|°GYP21 & GYP21P||Class III||Steroid-21-hydroxylases.|
|°G7a & G7b||Class III||Valyl-tRNA synthetase.|
|°HSP||Class III||Heat-shock protein.|
|LMP2 & LMP7||Class II||Proteasome-like subunits.|
|TAP1 & TAP2||Class II||Peptide transporter.|
|DMα & DMβ||Class II||Catalyzes binding of peptide to MHC; structurally similar to Class II MHC.|
|TNFα & TNFβ||Class III||Tumor necrosis factors α & β.|
Each region is highly polymorphic, meaning that it can have one of many different alleles.
There are several common mouse strains, and for the sake of efficiency their haplotypes (their set of K, IA, IE, S and D alleles) have been compressed into shorthand. For example, H-2k mice have all k alleles, H-2d mice have all d alleles and H-2b mice have all b alleles. Mice obviously have two chromosomes, so a H-2k/k mouse is one whose two chromosomes have both have all k alleles, and a H-2k/b is a heterozygote with one all-k-allele and one all-b-allele chromosome.
Also, note that the alleles of individual regions can be described -- for example, an H-2k/b mouse has Kk and Kb regions. Haplotypes are closely linked and new recombinant haplotypes rarely arise.
The MHC haplotype is responsible for whether a patient accepts an organ transplant as self or rejects it as foreign.
If a patient receives an organ transplant from a donor with a different MHC haplotype (for example, H-2b/b vs H-2k/k) then that organ is rejected as non-self. The only exception is if a heterozygote (for example, H-2b/k) receives an organ homozygous for one of its haplotypes (for example, H-2b/b or H-2k/k) because it recognizes that haplotype as self.
The Class I region is ∼2,000kb long and contains ∼20 genes. In humans, the Class I region is at the telomeric end of the HLA complex. In mice, the Class I region is split in two, with Class II and III genes in the middle. The Class I region contains HLA-A, HLA-B and HLA-B in humans, and H-2K, H-2D and sometimes H-2L in mice. In humans, there is a litany of Class I non-classical proteins: HLA-E, -F and -G; HFE; HLA-J and -X; and MICA, B, C, D and E. In mice, Class I non-classical proteins are encoded in H-2Q, -T and M regions.
Located on the centromeric end of the MHC region, the Class II MHC region is broken into HLA-DR, -DP and -DQ in humans and H-2IA and H-2IE in mice. Each region encodes multiple Class II α and β chains -- for example, HLA-DR encodes as many as four functional β chains. The multiple α and β chains combine, thereby increasing the diversity of Class II MHC molecules. There are also several non-classical Class II genes, all of which have limited polymorphism. Examples of murine non-classical Class II genes are Oα, Oβ, Mα and Mβ; and two human non-classical Class II genes have been identified, DM and DO.
Class III genes are located between Class I and Class II genes, and encode a variety of proteins. Although not encoding proteins directly related to the major histocompatibility complex itself, Class III genes are present in all vertebrates. Mutations in Class III genes frequently lead to disease.