title: The number of responding CD4 T cells and the dose of antigen conjointly determine the TH1/TH2 phenotype by modulating B7/CD28 interactions.
abstract: Our previous in vivo studies show that both the amount of Ag and the number of available naive CD4 T cells affect the Th1/Th2 phenotype of the effector CD4 T cells generated. We examined how the number of OVA-specific CD4 TCR transgenic T cells affects the Th1/Th2 phenotype of anti-SRBC CD4 T cells generated in vivo upon immunization with different amounts of OVA-SRBC. Our observations show that a greater number of Ag-dependent CD4 T cell interactions are required to generate Th2 than Th1 cells. We established an in vitro system that recapitulates our main in vivo findings to more readily analyze the underlying mechanism. The in vitro generation of Th2 cells depends, as in vivo, upon both the number of responding CD4 T cells and the amount of Ag. We demonstrate, using agonostic/antagonistic Abs to various costimulatory molecules or their receptors, that the greater number of CD4 T cell interactions, required to generate Th2 over Th1 cells, does not involve CD40, OX40, or ICOS costimulation, but does involve B7/CD28 interactions. A comparison of the level of expression of B7 molecules by APC and CD4 T cells, under different conditions resulting in the substantial generation of Th1 and Th2 cells, leads us to propose that the critical CD28/B7 interactions, required to generate Th2 cells, may directly occur between CD4 T cells engaged with the same B cell acting as an APC.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5A1, Canada; and rudulic@mcmaster.ca peter.bretscher@usask.ca.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Rudulier
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5A1, Canada; and.
authors.forename: K Kai
authors.initials: KK
authors.lastname: McKinstry
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5A1, Canada; and.
authors.forename: Ghassan A
authors.initials: GA
authors.lastname: Al-Yassin
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5A1, Canada; and.
authors.forename: David R
authors.initials: DR
authors.lastname: Kroeger
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5A1, Canada; and.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Bretscher
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D000941:Antigens / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology; D008807:Mice, Inbred BALB C; D053262:Receptors, OX40 / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D000941:Antigens; D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse