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) 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.
Laboratory of Immunobiology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Y
Y
Ghendler
M K
MK
Teng
J H
JH
Liu
T
T
Witte
J
J
Liu
K S
KS
Kim
P
P
Kern
H C
HC
Chang
J H
JH
Wang
E L
EL
Reinherz
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D014644:Genetic Variation; D006183:H-2 Antigens / Q000737:chemistry / Q000235:genetics; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology
D004268:DNA-Binding Proteins; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008024:Ligands; D009842:Oligopeptides; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; C064655:V(D)J recombination activating protein 2; D014764:Viral Proteins; D001613:beta 2-Microglobulin