title: OX40-mediated differentiation to effector function requires IL-2 receptor signaling but not CD28, CD40, IL-12Rbeta2, or T-bet.
abstract: Ag-specific CD4 T cells transferred into unirradiated Ag-bearing recipients proliferate, but survival and accumulation of proliferating cells is not extensive and the donor cells do not acquire effector functions. We previously showed that a single costimulatory signal delivered by an agonist Ab to OX40 (CD134) promotes accumulation of proliferating cells and promotes differentiation to effector CD4 T cells capable of secreting IFN-gamma. In this study, we determined whether OX40 costimulation requires supporting costimulatory or differentiation signals to drive acquisition of effector T cell function. We report that OX40 engagement drives effector T cell differentiation in the absence of CD28 and CD40 signals. Two important regulators of Th1 differentiation, IL-12R and T-bet, also are not required for acquisition of effector function in CD4 T cells responsive to OX40 stimulation. Finally, we show that CD25-deficient CD4 T cells produce little IFN-gamma in the presence of OX40 costimulation compared with wild type, suggesting that IL-2R signaling is required for efficient OX40-mediated differentiation to IFN-gamma secretion.
authors.affiliation: Department of Molecular Microbiology and Immunology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
authors.forename: Cortny A
authors.initials: CA
authors.lastname: Williams
authors.forename: Susan E
authors.initials: SE
authors.lastname: Murray
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Weinberg
authors.forename: David C
authors.initials: DC
authors.lastname: Parker
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation; D007371:Interferon-gamma / Q000378:metabolism; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000235:genetics / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000502:physiology*; D053262:Receptors, OX40 / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000502:physiology; D000098815:T-bet Transcription Factor
chemical_list: D018106:CD28 Antigens; D019013:CD40 Antigens; D053712:Interleukin-12 Receptor beta 2 Subunit; D015375:Receptors, Interleukin-2; D053262:Receptors, OX40; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma