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* Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030; and
Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329
We compared how CD4 vs CD8 cells attain the capacity to express the effector cytokine IFN-
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- 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- and TNF-
double-producing effectors rather than becoming tolerant. Despite this and the stronger tendency of CD8 compared with CD4 cells to differentiate into IFN--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.
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1 This work was supported by National Institutes of Health Grants AI057441 and CA109339 (to A.J.A.) and AI052108 (to A.T.V.).
2 Address correspondence and reprint requests to Dr. Adam J. Adler, Department of Immunology, Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut Health Center, Farmington, CT 06030-1601. E-mail address: aadler{at}up.uchc.edu
3 Abbreviations used in this paper: HA, hemagglutinin; AcH3, acetylated histone H3; ChIP, chromatin immunoprecipitation; LN, lymph node; NT, nontransgenic; PMA plus I, PMA plus ionomycin; CT, cycle threshold.
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