What are MHC molecules?
Firstly, just a quick reminder as to what MHC molecules are! MHC (Major Histocompatibility Complex) molecules, also known as HLA (Human Leukocyte Antigens) are present on the surface of many cells of the body, and help to present antigens to T-cells as well as to help T-cells distinguish "self" from "non-self." As such they are very important in helping to protect us from disease, but at the same time they're also the reason why transplants come with a risk of rejection.
Let's loop around to talking about T-cells! As mentioned in an earlier post, T-cells are very fussy and won't respond to seeing an antigen in its native form. Oh no, it has to be all chopped up and presented to them on a nice little MHC molecule. MHC molecules thus have a binding site where a peptide from an antigen can bind. An MHC molecule can bind a vast array of peptides, but only one at a time. MHC molecules also have some other polymorphic (i.e. "many forms") residues which serve as "self" markers. T-cell receptors are able to recognise both "self"-markers and peptides simultaneously; however, T-cell receptors, like B-cell receptors and antibodies, are all specific to only one peptide each.
One exception of the specificity rule that you should know about are bacterial superantigens. These are molecules that can bind to both MHC-II (NOT MHC-I) and CD4+ T-cells (helper T-cells) non-specifically. This, in turn, causes non-specific activation of CD4+, which in turn leads to a massive production of cytokines. This causes systemic toxicity, which is not particularly pleasant. Staphylococcal enterotoxins (SE), which are responsible for the symptoms of food poisoning, mainly operate via this mechanism.
Describe the expression and structure of MHC molecules
MHC molecules have two classes: class I and class II. Let's talk about them separately...
MHC-I
MHC-I are expressed on all nucleated cells (but not non-nucleated cells such as erythrocytes). They are most highly expressed in haematopoietic cells. They can bind peptides that are endogenously derived- that is, derived from stuff within the cell- in order to present peptides to cytotoxic T-cells. The cytotoxic T-cells can then kill the cell if need be (for example, if the cell has been hijacked by a virus and is now expressing viral proteins). The peptides bound are only around 8-10 amino acids long, with their ends "buried" within the structure of MHC-I.
MHC-I is made up of two chains: α and β. The α chain is much larger, and has three domains that are arranged in a sort of upside-down L-shape. The peptide binds between α1 and α2, which are on the "top" of the molecule (i.e. the side facing away from the cell membrane). α3 associates with the β chain (specifically β2-microglobulin) using non-covalent interactions. The two domains on top (α1 and α2) are α-helices, whereas the other domains are Ig-fold domains (also seen in antibodies, as mentioned here).
When cells containing MHC-I interact with CD8+ (cytotoxic) T-cells, the CD8 co-receptor can bind to the α2 and α3 regions of the MHC-I molecule. To my understanding, both the T-cell receptor and CD8+ co-receptor must interact with MHC-I for an effector response to occur.
MHC-II
MHC-II is only expressed on professional antigen-presenting cells such as B-cells, macrophages and dendritic cells. In contrast to MHC-I, they bind exogenous peptides, which are peptides derived from outside of the cell. MHC-II can bind slightly larger peptides that are around 13-18 amino acids long, but some can bind slightly longer peptides. The ends of these peptides are not buried in the structure of the MHC molecule.
Just like MHC-I, MHC-II has an α and a β chain. However, the two chains of MHC-II are more even in length. Each chain has two domains. α1 and β1 make up the peptide binding cleft and are made up of α-helices, whereas α2 and β2 are Ig-fold domains. The two chains associate with each other via non-covalent bonding.
When cells containing MHC-II interact with CD4+ (helper) T-cells, the CD4 co-receptor binds to the β1 and β2 regions of the MHC-II molecule.
Describe the gene organisation of MHC
Just for comparison, we're going to look at the gene organisation of MHC for both mice and humans.
Mice
In mice, MHC is called H-2, which is short for Histocompatibility-2. The α-chain of class I is encoded by genes called K, D and L (I'm not 100% sure about the mouse, but I know that in humans the β-chain is encoded on a different chromosome). The genes encoding H-2 class II are called IA and IE. IA and IE are Ir ("immune response") genes. Each of these has an α and β section. Nearby there is a closely related gene called M, which also has an α and β section, but does not encode class II. I'll talk more about the human counterpart of M (which is called DM) in a later post. Also located nearby on the chromosome are genes for LMP (Large Molecular Proteosome) and TAP (a peptide transporter) which I'll also tell you more about in a later post.
Humans
In humans, the α-chain of MHC-I is encoded by genes called A, B and C (as I just mentioned, the beta-chain is on a different chromosome), whereas MHC-II is encoded by DP, DQ and DR (each of which has an α and β section). Also located on the same chromosome is DM, which is kind of like the M gene in the mouse, as well as LMP and TAP genes, which are also like their counterparts in the mouse. In humans, the chromosome encoding all of these genes also encodes "class III" genes, which don't actually encode any MHC molecules. Instead, class III genes encode cytokines, complement and other proteins that are important in the immune response.
Describe the significance of MHC polymorphism
Polymorphism ("many forms") in the case of genes simply means that there's many different variants of a particular gene in the population. All of the genes encoding class I and class II have multiple different variants in the population. Some have very few variants, like DRα, which only has three, but some have a lot, like B, which has 1431. This variation is important because differences in the antigen-binding cleft can, in turn, lead to variation in how well or poorly MHC molecules are able to bind different peptides. Additionally, since MHC molecules are also "self" markers, this polymorphism also has implications for transplantations.
Now let's get into a new concept- haplotypes! You see, all of the MHC alleles on the same chromosome (A, B, C, DP, DQ, DR etc.- basically everything except for those coding for the β-chain of MHC-I) are inherited as a block (i.e. all from the same chromosome). These blocks of MHC alleles are called a "haplotype." You will get one haplotype from your mum and one from dad. All alleles on both chromosomes are expressed, as expression of MHC alleles is co-dominant.
Let's give an example, using mouse cells. Remember, their genes are KDL (for the α-chain) and IA and IE (for the β-chain). Your average mouse would've inherited two H-2 haplotypes, one from the mother and one from the father. Let's call the mother's haplotype m, and the father's one f. Hence it's going to have an Km allele, an Kf allele, an Dm allele, an Df allele, and so on and so forth. All of these will be expressed, so the mouse will have some α-chains with Km, some with Kf, etc. The same thing happens with IA and IE, but MHC-II genes are super special and α-chains can combine with β-chains from the other chromosome. Hence you can get IEαmβm, IEαmβf etc.
Now to talk a little bit about graft rejection! Let's use a hypothetical example in which you have one mouse that's homozygous for the m haplotype and one that's homozygous for the f haplotype. They will have children that are heterozygous for m and f. Now, if the child receives a transplantation from either of their parents, they will be fine. If they get a transplant from the mouse with the m haplotype, their m alleles will be totally cool with that- same thing for if they receive a transplant from the mouse with the f haplotype. However, the parents cannot receive transplants from the children: the f haplotype will be seen as foreign to the mouse that is homozygous for m, and vice versa.
Summary
Because tables are cool, here's a nice table summarising the differences between MHC-I and MHC-II:
| MHC-I | MHC-II | |
| Location | All nucleated cells | Professional antigen-presenting cells only |
| Origin of peptides | Endogenous | Exogenous |
| Length of peptides bound | 8-10 amino acids (ends buried) | 13-18+ amino acids (ends not buried) |
| Present peptides to: | CD8+ (cytotoxic) T-cells | CD4+ (helper) T-cells |
| Relative chain size | α-chain much longer | Roughly the same length |
| Location of peptide-binding cleft | Between α1 and α2 | Between α1 and β1 |
| Location of co-receptor binding site | CD8 co-receptor binds to α2 and α3 | CD4 co-receptor binds to β1 and β2 |
| Genes | K, D, L (mouse) A, B, C (human) (β on different chromosome) | IA and IE (mouse) DP, DQ, DR (human) |
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