Clonal selection and expansion

Formulated by Burnet (1957), clonal selection theory makes four postulates: (1) each lymphocyte bears receptors of a single specificity; (2) binding of antigen with sufficient affinity activates the cell; (3) the activated cell's progeny (a clone) carry receptors of the same specificity; and (4) lymphocytes bearing receptors for self antigens are removed during development. Antigen therefore does not instruct the receptor — it selects cells whose receptors already fit.

Generating the repertoire. Antigen-receptor genes exist as separate gene segments — V (variable), D (diversity, heavy-chain and TCR β/δ only) and J (joining) — that are cut and joined at random in each developing lymphocyte by the RAG1/RAG2 recombinase, guided by recombination signal sequences, and repaired by non-homologous end joining (requiring Artemis). Diversity comes from combinatorial choice of segments, pairing of two different chains (heavy with light; α with β), and especially junctional diversity — random nucleotide loss and the addition of N-nucleotides by terminal deoxynucleotidyl transferase (TdT) — concentrated in CDR3. The theoretical repertoire exceeds 10¹⁵ receptors; an individual actually carries ≈ 10⁷–10⁸ distinct T-cell clonotypes, so the naive precursor frequency for any one epitope is only ≈ 1 in 10⁵–10⁶ lymphocytes.

Expansion and contraction. A selected naive T cell divides every 6–8 hours for about a week; antigen-specific CD8 T cells may expand more than 10 000-fold, so that during infectious mononucleosis a large fraction of all circulating CD8 T cells can be specific for EBV. Once the antigen is cleared, ≈ 90–95% of effector cells die by apoptosis (contraction), leaving an enlarged population of memory cells. B cells additionally diversify after selection by somatic hypermutation in germinal centres (affinity maturation).