The Major Histocompatibility Complex
What MHC is, and why it exists ★★★
The name is a historical accident and it hides the function. MHC was discovered because of transplant rejection — 'histocompatibility' means tissue compatibility, and these were the genes that decided whether a graft took. But rejecting grafts is obviously not what they evolved for. Their real job is the one in the definition below, and it is the reason T cells can see anything at all.
A cluster of genes encoding membrane glycoproteins that display peptide antigen to T cells.Section I, 2020
A B cell reads antigen directly — the BCR touches the intact molecule. A T cell cannot: the TCR only recognises a peptide held in an MHC groove. Why impose that restriction?
Because a T cell's job is to police what is happening inside cells, and the inside of a cell is invisible from outside. MHC solves that by making every cell continuously display samples of its own internal protein content on its surface. MHC is a window into the cytoplasm. A CTL patrolling the body is reading those windows, and a cell making viral protein cannot help but advertise it.
Transplant rejection is simply the side effect: your T cells were educated on your MHC, so another person's MHC looks profoundly wrong to them.
- Define MHC. → A cluster of genes encoding membrane glycoproteins that display peptide antigen to T cells
- Why can't T cells read antigen directly? → The TCR only recognises peptide bound to MHC
- What is MHC's real biological purpose? → Displaying a cell's internal protein content for inspection
Genetic organisation ★★★
| Human — HLA | Mouse — H-2 | |
|---|---|---|
| Chromosome | Chromosome 6 | Chromosome 17 |
| Class I genes | HLA-A, HLA-B, HLA-C | K, D, L |
| Class I product | α chain of class I molecules | α chain |
| Class II genes | HLA-DP, HLA-DQ, HLA-DR | A, E |
| Class II product | α and β chains of class II molecules | α and β chains |
| Class III products | C4, C2, Bf, TNF, HSP70 | C4, C2, Bf, TNF |
The class III region is worth a moment because it is not about presentation at all. It encodes complement components C4, C2 and factor B — the classical and alternative pathway proteins from Unit 4 — plus TNF and heat-shock protein 70. So a single genetic region carries the peptide-display system and several of the effector molecules that act on what it reveals.
The MHC also contains the machinery for getting peptides into the molecules. Encoded in the class II region are LMP2 and LMP7 (proteasome subunits), TAP1 and TAP2 (the peptide transporter), and HLA-DM, HLA-DO and tapasin. There are also non-classical class I genes — HLA-E and HLA-G. You meet TAP and the proteasome again in Unit 11.
- Which chromosome carries human MHC? → Chromosome 6
- Name the class I genes. → HLA-A, HLA-B, HLA-C
- Name the class II genes. → HLA-DP, HLA-DQ, HLA-DR
- What does class III encode? → Complement C4, C2, Bf; TNF; HSP70
- Which chains do class I and class II genes produce? → Class I → α chain only; class II → α and β chains
- Name the non-classical class I genes. → HLA-E and HLA-G
Structure ★★★
| MHC class I | MHC class II | |
|---|---|---|
| Chains | One α chain (MHC-encoded) + β2-microglobulin (not MHC-encoded) | α chain and β chain, both MHC-encoded |
| Domains | α1, α2, α3 + β2m | α1, α2 + β1, β2 |
| Peptide-binding cleft | α1 + α2 | α1 + β1 |
| Co-receptor binds | CD8, at the α3 domain | CD4, at the β2 domain |
| Ig-superfamily domain | α3 | α2 and β2 |
TMU Lecture 10 slide 32 states both directly: peptide-binding domain — class I α1/α2, class II α1/β1.
Class I = one MHC chain → the groove must come from that one chain → α1 + α2. Its partner β2-microglobulin is a support, not a groove wall, and is not even MHC-encoded.
Class II = two MHC chains → one domain from each → α1 + β1.
And the co-receptors follow the same logic — each binds the second domain of the non-groove pair: CD8 to α3, CD4 to β2.
- Which chains make up MHC class I? → One α chain plus β2-microglobulin
- Which chains make up class II? → An α chain and a β chain, both MHC-encoded
- Where is the class I cleft? → α1 + α2
- Where is the class II cleft? → α1 + β1 — this is MCQ Q6
- Where does CD8 bind? → The α3 domain of class I
- Where does CD4 bind? → The β2 domain of class II
Who expresses what ★★★
| Expressed on | |
|---|---|
| MHC class I | ALL nucleated cells |
| MHC class II | Only a subset of haematopoietic cells — dendritic cells, macrophages (MΦ) and B cells — plus thymic stromal cells |
This also explains a clinical fact you already knew: blood transfusion is matched on ABO and Rh, not HLA, because the cells being transfused carry no HLA class I to match.
Ask why the two classes are distributed so differently and everything falls into place.
Class I is everywhere because any cell can be infected by a virus. Every nucleated cell must be able to report its own cytoplasm, so every nucleated cell carries class I and every one can be inspected — and killed — by a CD8⁺ CTL.
Class II is restricted because only a few cells are supposed to give orders. Engaging a CD4⁺ helper T cell starts an immune response, and that authority is deliberately confined to cells whose job is sampling the environment: dendritic cells, macrophages, B cells. You would not want a random liver cell able to initiate an immune response.
So: class I reports, class II recruits — and the distribution follows.
- Which cells express MHC class I? → All nucleated cells
- Which express class II? → DC, macrophages, B cells, and thymic stromal cells
- Why don't mature erythrocytes express class I? → They have no nucleus — this is MCQ Q7
- Why is transfusion matched on ABO/Rh rather than HLA? → Red cells carry no HLA class I
- Is class II on all nucleated cells? → No — that is True/False Q12, and the answer is False
Polymorphism and the properties of MHC ★★
- Polygeny — several different MHC genes (A, B, C; DP, DQ, DR), so every person has several different class I and class II molecules
- Polymorphism — multiple alleles at each locus within the species. HLA-A has 303 alleles, HLA-B 559, HLA-C 150, HLA-DRB 440
- Co-dominance — both maternal and paternal gene products are expressed in the same cell; there is no allelic exclusion
- Haplotype — the particular combination of MHC alleles on a single chromosome, transmitted as a single unit in most cases
- Linkage disequilibrium — the difference between the observed frequency of a particular allele combination and the frequency expected from the individual allele frequencies
Note carefully where the variation lives. Antibody diversity is generated within each person — you make billions of different BCRs. MHC diversity is not: you have only a handful of MHC molecules, and they are the same in every cell of your body. The variation is between people.
That is a defence at the level of the population. A pathogen that evolves a peptide repertoire invisible to one person's MHC will still be presented perfectly well by someone else's — so no single pathogen can escape the whole species at once. Polymorphism protects humanity rather than the individual, and the price the individual pays is that organs cannot be swapped freely.
Co-dominance is the individual's hedge: expressing both parents' alleles doubles the number of different MHC molecules you carry, and so widens the range of peptides you can present.
- Define polymorphism. → The presence of multiple alleles at a genetic locus within the species
- What is co-dominance in MHC? → Both maternal and paternal products are expressed in the same cell; no allelic exclusion
- Define haplotype. → The particular combination of MHC alleles on a single chromosome, inherited as a unit
- Define linkage disequilibrium. → The difference between observed and expected frequency of an allele combination
- Name the five properties of MHC. → Polygeny, polymorphism, co-dominance, haplotype, linkage disequilibrium
How peptides bind ★★★
| Class I | Class II | |
|---|---|---|
| Peptide-binding domain | α1 / α2 | α1 / β1 |
| Nature of the cleft | Closed | Open |
| Peptide size | 8–10 amino acids | 13–18 amino acids |
| Anchor residues | At both ends of the peptide | Distributed along the length of the peptide |
The closed-versus-open distinction explains everything else in the table. A closed cleft is sealed at both ends, so the peptide must fit exactly — hence the tight 8–10 residue range and anchors gripping both termini. An open cleft lets the peptide hang out at either end, so its length is not constrained; 13–18 residues is typical but longer peptides are tolerated, and the anchors are spaced along its length rather than at the ends.
Structurally related residues by which a peptide binds into the MHC groove. The anchor residues differ between different alleles of MHC but are similar for all peptides binding the same MHC molecule — so each MHC allele has its own characteristic peptide-binding motif.
This is the elegant part. Each MHC allele demands only a couple of specific anchor residues at fixed positions; everything between them is unconstrained. So a single MHC molecule accepts a whole family of peptides sharing that motif — thousands of them, from any protein.
Contrast an antibody, which binds one epitope with high specificity. MHC is deliberately the opposite: low specificity, enormous breadth. That has to be true, because a handful of MHC molecules must cover every peptide from every pathogen you will ever meet. The specificity is supplied afterwards, by the TCR reading the combination of peptide and MHC.
- Class I peptide length, and class II? → 8–10 aa; 13–18 aa
- Which cleft is closed and which is open? → Class I closed; class II open
- Where are anchor residues in class I? → At both ends of the peptide
- Where in class II? → Distributed along the peptide's length
- Do anchor residues differ between MHC alleles? → Yes — but they are similar for all peptides binding one MHC molecule
Functions of MHC molecules ★★
- Bind and present antigenic peptides derived from pathogens, and display them to T cells
- Impose MHC restriction on the interaction between antigen-presenting cells and T cells
- Take part in T-cell differentiation in the thymus — positive and negative selection (Unit 7)
Function 3 is worth linking back explicitly. Positive selection works by presenting self-peptide–MHC to double-positive thymocytes; the ones that bind with proper affinity survive and become restricted to that MHC. So MHC does not merely constrain the mature T cell — it created the constraint during development. This is why Unit 7 said the MHC haplotype of the thymus determines a T cell's restriction for life.
- Name the three functions of MHC. → Present peptide to T cells; impose MHC restriction; direct thymic T-cell differentiation
- How does MHC create restriction rather than just impose it? → Positive selection selects thymocytes on the thymus's own MHC
Revision layer
The exam map for this unit
| Section | Item | From |
|---|---|---|
| I. Definitions | MHC — set 2020 | §1 |
| III. MCQ Q6 | Class II cleft is between α1 and β1 | §3 |
| III. MCQ Q7 | Mature erythrocytes lack HLA class I | §4 |
| IV. True/False Q12 | Class II on all nucleated cells — F | §4 |
Class I versus class II — the master table
| Class I | Class II | |
|---|---|---|
| Genes | HLA-A, B, C | HLA-DP, DQ, DR |
| Chains | α + β2-microglobulin | α + β |
| Cleft | α1 + α2 | α1 + β1 |
| Cleft nature | Closed | Open |
| Peptide | 8–10 aa | 13–18 aa |
| Anchors | Both ends | Along the length |
| Co-receptor | CD8 at α3 | CD4 at β2 |
| Expressed on | All nucleated cells | DC, macrophage, B cell, thymic stroma |
| Presents to | CD8⁺ CTL | CD4⁺ helper T cell |
| Antigen source | Endogenous (cytosolic) | Exogenous (vesicular) |
Class I × CD8 = 8. Class II × CD4 = 8. Multiply the class number by the co-receptor number and you always get eight. It fixes the single most confusable pairing in immunology, and from it the rest follows: class I → CD8 → CTL → endogenous antigen → all nucleated cells.
- Define MHC. → A cluster of genes encoding membrane glycoproteins that display peptide antigen to T cells
- Which chromosome, and which genes? → Chromosome 6; class I A/B/C, class II DP/DQ/DR, class III C4/C2/Bf/TNF
- Class I cleft and class II cleft? → α1+α2; α1+β1
- Which is closed, and what peptide length? → Class I, closed, 8–10 aa; class II open, 13–18 aa
- Which cells lack class I? → Non-nucleated ones — mature erythrocytes
- Which cells carry class II? → DC, macrophage, B cell, thymic stroma
- Five properties of MHC? → Polygeny, polymorphism, co-dominance, haplotype, linkage disequilibrium
- Class-to-co-receptor rule? → Class I × CD8 = 8; class II × CD4 = 8