CD28-B7 interactions function to co-stimulate clonal deletion of double-positive thymocytes.
Negative selection of thymocytes only occurs if next to signals through the TCR, additional antigen-presenting cell (APC)-derived signals are also provided. It has been unclear which molecular interactions lead to the generation of these signals. In particular, the involvement of CD28 and its ligands B7-1 and B7-2 has been controversial. In the present study, we re-address this issue and first confirm that cross-linking CD28 molecules on thymocytes can indeed complement TCR-derived signals for induction of deletion upon TCR engagement with antibodies. Furthermore, we extend these findings by documenting that also peptide agonist-induced deletion can be co-stimulated by antibody-mediated engagement of CD28. Additionally, blocking B7-1 or B7-2 reduces negative selection induced by both anti-CD3 and peptide agonist in suspension cultures and in fetal thymic organ culture. At the same time, prominent co-stimulation of TCR-induced deletion could be provided by a B7-negative cell line. Together these results definitively demonstrate that CD28-B7 interactions can function to co-stimulate induction of clonal deletion, while yet to be identified B7-independent co-stimulatory signals can fulfil this function as well.
Amsen
D
D
Division of Immunology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Amsterdam, The Netherlands.
Kruisbeek
A M
AM
D000818:Animals; D018122:B7-1 Antigen / Q000494:pharmacology*; D018106:CD28 Antigens / Q000494:pharmacology*; D002478:Cells, Cultured; D017637:Clonal Deletion / Q000187:drug effects*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004357:Drug Synergism; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects*
D018122:B7-1 Antigen; D018106:CD28 Antigens; D003432:Cross-Linking Reagents