title: Changes in the strength of co-stimulation through the B7/CD28 pathway alter functional T cell responses to altered peptide ligands.
abstract: T cells require a TCR and a co-stimulatory signal for activation. We have examined the effect of the strength of TCR and co-stimulatory signals on proliferation 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, Chinese hamster ovary cell transfectants that express different levels of the B7-1 molecule with similar levels of MHC class II. Our results show that the level of co-stimulation has a profound effect on the response to an antigen, 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 absolute 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. These results show that the level of expression of co-stimulatory molecules will profoundly regulate T cell clonal expansion and effector functions.
authors.affiliation: Center for Neurologic Diseases, Department of Neurology, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: A
authors.initials: A
authors.lastname: Murtaza
authors.forename: V K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: G J
authors.initials: GJ
authors.lastname: Freeman
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D016466:CHO Cells; D002999:Clone Cells; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D008024:Ligands; D051379:Mice; D008815:Mice, Inbred Strains; D018991:Myelin Proteolipid Protein / Q000276:immunology*; D009842:Oligopeptides / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D020239:Receptor Cross-Talk; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000276:immunology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D018106:CD28 Antigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D018991:Myelin Proteolipid Protein; D009842:Oligopeptides; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C435023:myelin proteolipid protein (139-151)