CD28-B7 INTERACTIONS FUNCTION TO CO-STIMULATE CLONAL DELETION OF DOUBLE-POSITIVE THYMOCYTES

Negative selection of thymocytes only occurs if next to signals throug h the TCR, additional antigen-presenting cell (APC)-derived signals ar e 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 pre sent study, we re-address this issue and first confirm that cross-link ing CD28 molecules on thymocytes can indeed complement TCR-derived sig nals for induction of deletion upon ICR engagement with antibodies. Fu rthermore, we extend these findings by documenting that also peptide a gonist-induced deletion can be co-stimulated by antibody-mediated enga gement of CD28. Additionally, blocking B7-1 or B7-2 reduces negative s election induced by both anti-CD3 and peptide agonist in suspension cu ltures and in fetal thymic organ culture. At the same time, prominent co-stimulation of TCR-induced deletion could be provided by a B7-negat ive cell line. Together these results definitively demonstrate that CD 28-B7 interactions can function to co-stimulate induction of clonal de letion, while yet to be identified B7-independent co-stimulatory signa ls can fulfil this function as well.