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T lineage repertoire is shaped by T cell receptor (TCR)-dependent positive and negative thymic selection processes. Using TCR-transgenic (N15tg) beta2-microglobulin-deficient (beta2m-/-) RAG-2(-/-) H-2(b) mice specific for the VSV8 (RGYVYQGL) octapeptide bound to Kb, 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/Kb was determined and refined to 2.1 A for comparison with the VSV8/Kb structure at similar resolution. Aside from changes on the p4 side chain of L4 and the resulting alteration of the exposed Kb 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/Kb complex, moreover, it appears that the germ-line Valpha repertoire contributes in a significant way to positive selection.","bibjson":{"author":[{"initials":"Y","lastname":"Ghendler","name":"Ghendler Y"},{"initials":"MK","lastname":"Teng","name":"Teng MK"},{"initials":"JH","lastname":"Liu","name":"Liu JH"},{"initials":"T","lastname":"Witte","name":"Witte T"},{"initials":"J","lastname":"Liu","name":"Liu J"},{"initials":"KS","lastname":"Kim","name":"Kim KS"},{"initials":"P","lastname":"Kern","name":"Kern P"},{"initials":"HC","lastname":"Chang","name":"Chang HC"},{"initials":"JH","lastname":"Wang","name":"Wang JH"},{"initials":"EL","lastname":"Reinherz","name":"Reinherz EL"}],"identifier":[{"id":"10.1073/pnas.95.17.10061","type":"doi"},{"id":"9707600","type":"pubmed"}],"issue":["17"],"journal":{"iso_abbreviation":"Proc. Natl. Acad. Sci. 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