Changes in the strength of co-stimulation through the B7/CD28 pathway alter functional T cell responses to altered peptide ligands

T cells require a TCR and a co-stimulatory signal for activation. We have e xamined the effect of the strength of TCR and co-stimulatory signals on pro liferation and production of cytokines by differentiated T cell clones. The TCR signal was varied using antigen dose and altered peptide ligands. The co-stimulatory signal was varied by using as antigen-presenting cells, Chin ese hamster ovary cell transfectants that express different levels of the B 7-1 molecule with similar levels of MHC class II. Our results show that the level of cc-stimulation has a profound effect on the response to an antige n, and that a strong co-stimulatory signal can convert a weak agonist into a full agonist and an agonist into a superagonist. Antigenicity is not abso lute but a function of the strengths of the TCR and co-stimulatory signals. Increasing the strength of co-stimulation can lower antigen concentration required for maximal proliferative responses by T cell clones by 5 log. The se results show that the level of expression of co-stimulatory molecules wi ll profoundly regulate T cell clonal expansion and effector functions.