Locus-specific somatic hypermutation in germinal centre T cells

Abstract

Somatic hypermutation and affinity-driven selection of active immunoglobulin genes occur in germinal centres (GCs), resulting in the generation of high-affinity memory B cells. In contrast, T lymphocytes do not require the germinal centre microenvironment to establish memory and the T-cell antigen receptor (TCR) genes, though homologous to immunoglobulin genes, are believed to be incapable of hypermutation. Here we present direct evidence that the small population of antigen-specific T cells that are recruited into splenic GCs acquire mutations in the variable region of genes encoding TCR alpha-chains (V alpha) but not those of beta-chains. These locus-specific mutations reach frequencies comparable to mutated immunoglobulin VH exons recovered from the same site and exhibit similar substitution biases and DNA strand polarity. T cells bearing identical mutations appear in multiple GCs, raising the possibility that some cells bearing mutant TCRs may re-enter the peripheral lymphocyte pool.