Antigen processing and presentation

MHC class I pathway (endogenous antigens). Proteins in the cytosol — normal self-proteins, but also viral or mutated tumour proteins — are tagged with ubiquitin and degraded by the proteasome (replaced by the more efficient immunoproteasome under IFN-γ). Peptides are pumped into the endoplasmic reticulum by TAP (transporter associated with antigen processing), loaded onto newly made class I heavy chain–β2-microglobulin complexes by the peptide-loading complex (tapasin, calreticulin, ERp57), and carried via the Golgi to the cell surface, where CD8 T cells inspect them. Every nucleated cell therefore continuously reports on what it is making.

MHC class II pathway (exogenous antigens). Antigen-presenting cells ingest proteins by phagocytosis, macropinocytosis or receptor-mediated endocytosis (via the BCR in B cells); acidified endolysosomes degrade them with cathepsins. Newly synthesised class II molecules leave the ER bound to the invariant chain (Ii, CD74), which blocks the groove and targets them to these compartments; Ii is digested, leaving the CLIP fragment in the groove until HLA-DM exchanges it for an antigenic peptide. The peptide–class II complex is then displayed to CD4 T cells. Cross-presentation, chiefly by cDC1 dendritic cells, routes exogenous antigen into the class I pathway, allowing priming of CD8 T cells against viruses that do not infect DCs and against tumours.

Activation of naive T cells requires three signals from the antigen-presenting cell (a mature dendritic cell): signal 1 — TCR binding peptide–MHC with the CD4 or CD8 co-receptor, organised into an immunological synapse; signal 2 — co-stimulation, principally B7-1/B7-2 (CD80/CD86) binding CD28 (CD40–CD40L amplifies it); and signal 3 — polarising cytokines. Signal 1 without signal 2 induces anergy. Activated T cells later express CTLA-4 (binds B7 more strongly than CD28 and inhibits) and PD-1 (binds PD-L1/PD-L2), "checkpoints" that terminate responses.