Differential thymic selection outcomes stimulated by focal structural alteration in peptide/major histocompatibility complex ligands

The T lineage repertoire is shaped by T cell receptor (TCR)-dependent positive and negative thymic selection processes. Using TCR-transgenic (N15tg) β(2)-microglobulin-deficient (β(2)m(−/−)) RAG-2(−/−) H-2(b) mice specific for the VSV8 (RGYVYQGL) octapeptide bound to K(b), we identified a single weak agonist peptide variant V4L (L4) inducing phenotypic and functional T cell maturation. The cognate VSV8 peptide, in contrast, triggers negative selection. The crystal structure of L4/K(b) was determined and refined to 2.1 Å for comparison with the VSV8/K(b) structure at similar resolution. Aside from changes on the p4 side chain of L4 and the resulting alteration of the exposed K(b) Lys-66 side chain, these two structures are essentially identical. Hence, a given TCR recognizes subtle distinctions between highly related ligands, resulting in dramatically different selection outcomes. Based on these finding and the recent structural elucidation of the N15-VSV8/K(b) complex, moreover, it appears that the germ-line Vα repertoire contributes in a significant way to positive selection.