7.1 The molecules #
7.1.1 Two scaffolds, two T cells #
T-cell receptors do not bind free antigen. Zinkernagel and Doherty showed in 1974 that a T cell recognises antigen only together with self MHC: the receptor contacts peptide and the MHC protein holding it. Class I is a heavy chain plus ฮฒ2-microglobulin, which is encoded outside the MHC. The groove is closed, peptides are about 8โ10 residues with allele-specific anchors, and CD8 binds the ฮฑ3 domain. Nearly every nucleated cell expresses class I, so a CD8 cell can survey it. Class II is an ฮฑฮฒ dimer, both chains in the MHC, with an open groove and peptides often about 13โ25 residues. CD4 binds class II. Expression is limited to dendritic cells, macrophages, B cells, and thymic epithelium, and IFN-ฮณ can induce it elsewhere.
| Feature | MHC class I | MHC class II |
|---|---|---|
| Chains | ฮฑ plus ฮฒ2-microglobulin | ฮฑ plus ฮฒ |
| Peptide | Closed groove; about 8โ10 residues | Open groove; often about 13โ25 residues |
| Expressed on | Nearly all nucleated cells | Dendritic cells, macrophages, B cells, thymic epithelium |
| Peptide source | Cytosol, plus cross-presented antigen | Endosomes and phagosomes |
| T cell | CD8 | CD4 |
| Classical HLA loci | HLA-A, HLA-B, HLA-C | HLA-DP, HLA-DQ, HLA-DR |
7.1.2 Codominance, polymorphism, and why both matter #
Both haplotypes are expressed, so a heterozygote presents a wider set of peptides. The loci are the most polymorphic in the human genome, and the differences sit in the peptide-binding pockets: a peptide that fits one person’s HLA-A may be invisible to a neighbour. For a population that is a benefit, because a pathogen that escapes one set of grooves still meets others. Particular alleles also present disease-related peptides well, as with HLA-B27 in ankylosing spondylitis and HLA-DQ2 and HLA-DQ8 in coeliac disease. For transplantation the same polymorphism is the obstacle. The loci travel as a haplotype, so siblings have a one-in-four chance of sharing both.
7.1.3 Names #
The human MHC is HLA, on chromosome 6. Classical class I genes are HLA-A, HLA-B, and HLA-C. ฮฒ2-microglobulin is on chromosome 15. Class II genes are HLA-DP, HLA-DQ, and HLA-DR, and one DR haplotype often encodes an extra ฮฒ chain, hence two DR molecules.
7.2 Processing pathways #
The study of Processing pathways provides fundamental principles governing cellular architecture, molecular interactions, and physiological regulation.
Il-18 Signaling Pathway (Homo Sapiens)
7.2.1 The cytosolic route to MHC class I #
Class I reports on the cytosol. Ubiquitinated proteins are degraded by the proteasome; IFN-ฮณ induces alternative subunits, including LMP2 and LMP7 in the MHC, that favour peptides suited to class I. TAP1 and TAP2 pump those peptides into the endoplasmic reticulum. A loading complex that includes tapasin holds empty class I until a suitable peptide completes folding with ฮฒ2-microglobulin, and the complex travels the secretory pathway. Empty class I is unstable. Loss of TAP or tapasin leaves little surface class I and few CD8 cells.
7.2.2 The endosomal route to MHC class II #
Class II reports on material taken up from outside, including antigen internalised by a B-cell receptor. The dimer assembles with invariant chain (CD74), which fills the groove so class I peptides cannot bind and targets the complex to a late endosome. Proteases degrade the invariant chain to CLIP. HLA-DM catalyses CLIP release and loading of a stable endosomal peptide. Mature dendritic cells then slow further exchange, so they keep displaying the peptides captured at the moment they were activated.
7.2.3 Cross-presentation #
An epithelial cell infected by a virus can be killed by an effector CD8 cell, but it cannot prime a naive one: it supplies neither costimulation nor traffic into the paracortex. Dendritic cells prime by placing antigen they acquired from outside onto their own class I. That is cross-presentation, done best by the cDC1 subset, either by feeding protein into the cytosol for proteasome and TAP or by loading class I inside a vesicle. The result is a CD8 response against a virus the dendritic cell never let replicate, and against tumour debris.
7.3 Key terms, summary, and self-check #
Key terms. MHC restriction; ฮฒ2-microglobulin; codominance; polymorphism; haplotype; HLA-A; HLA-B; HLA-C; HLA-DP; HLA-DQ; HLA-DR; TAP; tapasin; invariant chain; CLIP; HLA-DM; cross-presentation.
Summary. Class I on nearly all nucleated cells presents short cytosolic peptides to CD8 cells. Class II on professional antigen-presenting cells presents longer endosomal peptides to CD4 cells. Both haplotypes are expressed, and polymorphic grooves slow pathogen escape in a population and cause graft rejection between people. Cytosolic proteins reach class I through the proteasome and TAP. Endosomal proteins reach class II after HLA-DM exchanges CLIP for peptide. Cross-presentation lets dendritic cells prime CD8 cells against antigen they did not synthesise.
Self-check.
1. Compare class I and class II on peptide length, expressing cells, and T-cell partner.
2. Why does MHC polymorphism help a population and hinder a transplant?
3. What does TAP transport, and what is CLIP doing in the class II groove?
4. What does HLA-DM do that invariant chain does not?
5. What failure of priming follows if dendritic cells cannot cross-present?
