Antigen Processing and MHC Peptide Presentation

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:

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