Competition for specific intrathymic ligands limits positive selection in a TCR transgenic model of CD4+ T cell development.
Efficient positive selection of a broad repertoire of T cells is dependent on the presentation of a diverse array of endogenous peptides on MHC molecules in the thymus. It is unclear, however, whether the development of individual TCR specificities is influenced by the abundance of their selecting ligands. To examine this, we analyzed positive selection in a transgenic mouse carrying a TCR specific for the human CLIP:I-Ab class II complex. We found that these mice exhibit significantly reduced CD4+ T cell development compared with two other transgenic mice carrying TCRs selected on I-Ab. Moreover, many of the selected cells in these mice express endogenous and transgenic receptors as a consequence of dual TCRalpha expression. Dramatic enhancement of the selection efficiency is observed, however, when fewer transgenic cells populate the thymus in mixed bone marrow chimeras. These results suggest that positive selection is limited by the availability of selecting peptides in the thymus. This becomes apparent when large numbers of thymocytes compete for such peptides in TCR transgenic animals. Under such conditions, thymocytes appear to undergo further TCRalpha gene rearrangement to produce a receptor that may be selected more efficiently by other thymic self-peptides.
Wong
P
P
Howard Hughes Medical Institute, Department of Immunology, University of Washington School of Medicine, Seattle 98195, USA.
Goldrath
A W
AW
Rudensky
A Y
AY
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D001667:Binding, Competitive / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D019426:Integrases; D007700:Kinetics; D008024:Ligands; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018448:Models, Immunological; D010455:Peptides / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D045522:Recombinases; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D000944:Antigens, Differentiation, B-Lymphocyte; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D010455:Peptides; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D045522:Recombinases; C064655:V(D)J recombination activating protein 2; C045084:invariant chain; D004254:DNA Nucleotidyltransferases; D019426:Integrases; C115006:integron integrase IntI1