Disparate peptide-dependent thymic selection outcomes in beta2M-deficient mice versus TAP-1-deficient mice: implications for repertoire formation.
Fetal thymic organ cultures of N15-transgenic RAG-2-/- H-2b mice on normal, beta-2 microglobulin (beta2M)-/- or transporter associated with antigen processing (rAP-1)-/- MHCl-deficient backgrounds were used to examine differentiation of thymocytes bearing a TCR specific for a viral peptide bound to H-2Kb. Strong agonists mediate negative selection in all mice whereas weak agonists are positively selecting in beta2MW-/- mice but negatively selecting on TAP-1-/- or normal backgrounds. Very weak agonists and very weak antagonists are generally without effect in beta2M-/- mice yet foster differentiation in TAP-1-/- animals. The 20-40-fold reduction in beta2M4-/- thymic H-2Kb surface expression suggests that the avidity of the TCR for peptide-MHCI accounts for these differences, consistent with effects of TCR density and individual thymic-peptide abundance in peptide-MHC complexes. TCR-self-MHC interaction dominates Kb-based selection, subtly modulated by peptides as revealed by X-ray crystallography.
Sasada
Tetsuro
T
Laboratory of Immunobiology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Yang
Yuting
Y
Lai
Char-Chang
CC
Touma
Maki
M
Clayton
Linda K
LK
Liu
Jin-huan
JH
Parisini
Emilio
E
Wang
Jia-huai
JH
Reinherz
Ellis L
EL
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology; D017637:Clonal Deletion / Q000502:physiology*; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000172:deficiency; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D018655:Lymphocyte Count; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008958:Models, Molecular; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D055672:Static Electricity; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology*; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology; D001613:beta 2-Microglobulin / Q000172:deficiency*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000956:Antigens, Viral; D004268:DNA-Binding Proteins; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008024:Ligands; D046911:Macromolecular Substances; D010446:Peptide Fragments; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse; C064655:V(D)J recombination activating protein 2; D001613:beta 2-Microglobulin