title: Self-antigen prevents CD8 T cell effector differentiation by CD134 and CD137 dual costimulation.
abstract: We compared how CD4 vs CD8 cells attain the capacity to express the effector cytokine IFN-gamma under both immunogenic and tolerogenic conditions. Although the Ifng gene locus was epigenetically repressed in naive Ag-inexperienced CD4 cells, it had already undergone partial remodeling toward a transcriptionally competent configuration in naive CD8 cells. After TCR stimulation, CD8 cells fully remodeled the Ifng locus and gained the capacity to express high levels of IFN-gamma more rapidly than CD4 cells. Enforced dual costimulation through OX40 and 4-1BB redirected CD8 cells encountering soluble exogenous peptide to expand and differentiate into IFN-gamma and TNF-alpha double-producing effectors rather than becoming tolerant. Despite this and the stronger tendency of CD8 compared with CD4 cells to differentiate into IFN-gamma-expressing effectors, when parenchymal self-Ag was the source of tolerizing Ag, enforced dual costimulation selectively boosted expansion but did not push effector differentiation in CD8 cells while both expansion and effector differentiation were dramatically boosted in CD4 cells. Notably, enforced dual costimulation was able to push effector differentiation in CD8 cells encountering cognate parenchymal self-Ag when CD4 cells were simultaneously engaged. Thus, the ability of enforced OX40 plus 4-1BB dual costimulation to redirect CD8 cells to undergo effector differentiation was unexpectedly influenced by the source of tolerizing Ag and help was selectively required to facilitate CD8 cell effector differentiation when the tolerizing Ag derived from self.
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030-1601, USA.
authors.forename: Suman
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Meixiao
authors.initials: M
authors.lastname: Long
authors.forename: Harry Z
authors.initials: HZ
authors.lastname: Qui
authors.forename: Adam T
authors.initials: AT
authors.lastname: Hagymasi
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Slaiby
authors.forename: Marianne A
authors.initials: MA
authors.lastname: Mihalyo
authors.forename: Hector L
authors.initials: HL
authors.lastname: Aguila
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mittler
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Vella
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Adler
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000276:immunology; D040641:Quantitative Trait Loci / Q000276:immunology; D053262:Receptors, OX40 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology*
chemical_list: D001324:Autoantigens; D010455:Peptides; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; C505717:Tnfrsf4 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma