B7/CD28 but not LFA-3/CD2 interactions can provide 'third-party' co-stimulation for human T-cell activation

The requirement for co-stimulation in T-cell activation has become firmly established, whilst the precise identity of the molecules involved remains uncertain. Some of the major co-stimulatory molecules include ICAM-1, LFA-3 and B7. We have investigated the abilities of both LFA-3 and B7 to co-stimulate T-cell proliferation under a number of conditions using transfected Chinese hamster ovary cells. Using anti-CD3 antibodies we observed that B7 but not LFA-3 transfectants were capable of co-stimulating proliferation in purified peripheral blood T cells. In addition, both LFA-3 and B7 could induce proliferation in response to phytohaemagglutinin (PHA) and we obtained additive effects using both B7 and LFA-3 together. Using the superantigen staphylococcal enterotoxin B (SEB), we observed that presentation to purified T cells required the presence of class II-positive transfectants and that sensitivity to antigen was increased approximately 100-fold by the co-transfection of either B7 or LFA-3. However, when co-stimulatory molecules were provided by cells separate from those engaging the T-cell receptor (TcR), only B7 was capable of enhancing proliferation. Kinetic studies which investigated the time dependence for co-stimulation revealed that T cells responding to anti-CD3 antibodies required the B7 co-stimulation within the first few hours, for proliferation to be effective. Our data differentiate between the co-stimulatory abilities of B7 and LFA-3 and support the concept of a pivotal role for B7 in T-cell proliferation.