DIFFERING ROLES FOR B7 AND INTERCELLULAR-ADHESION MOLECULE-1 IN NEGATIVE SELECTION OF THYMOCYTES

To ensure self tolerance, immature thymocytes with high binding affini ty for self peptides linked to major histocompatibility complex (MHC) molecules are eliminated in situ via apoptosis (negative selection). T he roles of two costimulatory molecules, B7-1 and intercellular adhesi on molecule-1 (ICAM-1), in negative selection was examined by studying apoptosis of T cell receptor transgenic CD4(+)8(+) thymocytes culture d with specific peptides presented by MHC class I-transfected Drosophi la cells. When coexpressed on these cells, B7-1 and ICAM-1 act thymocy tes. When act synergistically and cause strong class I-restricted nega tive selection of expressed separately. However, B7-1 and ICAM-1 displ ay opposite functions. negative selection is augmented by B7-1, but is inhibited by ICAM-1. It is notable that B7-1 is expressed selectively in the thymic medulla, whereas ICAM-1 is expressed throughout the thy mus. Because of this distribution, the differing functions of B7-1 and ICAM-1 may dictate the sites of positive and negative selection. Thus , in the cortex, the presence of ICAM-1, but not B7-1, on the cortical epithelium may preclude or reduce negative selection and thereby prom ote positive selection. Conversely, the combined expression of B7-1 an d ICAM-1 may define the medulla as the principal site of negative sele ction.