MHC peptide presentation is the fundamental mechanism by which the adaptive immune system monitors cellular health and detects pathogens.
The MHC System
Major Histocompatibility Complex
MHC molecules are cell surface glycoproteins that display peptide fragments to T cells:
| Class | Expression | Peptide Source | T Cell Type |
| MHC Class I | All nucleated cells | Intracellular proteins | CD8+ (cytotoxic) |
| MHC Class II | Professional APCs | Extracellular proteins | CD4+ (helper) |
MHC Class I Pathway
Peptide Generation
1. **Proteasomal degradation** — Cytoplasmic proteins cleaved by the 26S proteasome
2. **Immunoproteasome** — IFN-γ induces specialized subunits (LMP2, LMP7, MECL-1)
3. **Result** — Peptides of 8-11 amino acids (optimal: 9-mers)
Peptide Transport
- **TAP (Transporter Associated with Antigen Processing)**
- Heterodimer of TAP1 and TAP2
- ATP-dependent transport into ER lumen
- Prefers peptides with hydrophobic C-termini
MHC Loading
1. Peptide binds MHC Class I heavy chain + β2-microglobulin
2. Tapasin, ERp57, and calreticulin assist loading
3. Stable peptide-MHC complex traffics to cell surface
4. Display to CD8+ T cells
MHC Class II Pathway
Antigen Uptake
- Phagocytosis, endocytosis, or autophagy
- Pathogens internalized into endosomes
Peptide Generation
- Endosomal proteases (cathepsins B, D, L, S)
- Generates peptides of 13-25 amino acids
- Less precise length requirements than Class I
MHC Loading
1. MHC II synthesized with invariant chain (Ii, CD74)
2. Ii occupies peptide groove, prevents premature binding
3. In endosome, Ii degraded to CLIP fragment
4. HLA-DM catalyzes CLIP exchange for antigenic peptide
5. Peptide-MHC II displayed to CD4+ T cells
Peptide Binding Rules
Anchor Residues
MHC molecules have specific pockets that accommodate "anchor" residues:
- Position 2 and C-terminus most critical for Class I
- Different HLA alleles prefer different anchors
- Example: HLA-A*02:01 prefers Leu/Met at P2, Val/Leu at C-terminus
Binding Affinity
- Strong binders: IC50 < 50 nM
- Weak binders: IC50 50-500 nM
- Non-binders: IC50 > 500 nM
Immunological Significance
Self-Tolerance
- Thymic selection eliminates T cells reactive to self-peptides
- Peripheral tolerance maintains non-reactivity
Pathogen Detection
- Viral/bacterial peptides trigger immune response
- Single amino acid changes can alter immunogenicity
Cancer Immunology
- **Neoantigens** — Mutated peptides unique to tumors
- Basis for personalized cancer vaccines
- Checkpoint inhibitors unleash anti-tumor T cells
Therapeutic Applications
Peptide Vaccines
- Synthetic peptides mimicking pathogen epitopes
- Multi-epitope vaccines for broad coverage
Neoantigen Therapy
- Sequence tumor mutations
- Predict MHC binding
- Vaccinate with tumor-specific peptides
Tolerance Induction
- Deliver self-peptides to treat autoimmunity
- Antigen-specific immunotherapy
