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Cutting Edge: Chromatin Remodeling as a Molecular Basis for the Enhanced Functionality of Memory CD8 T Cells¹

John K. Northrop^*, Andrew D. Wells^, and Hao Shen^2,*

^* Department of Microbiology and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Joseph Stokes, Jr. Research Institute, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104

Memory CD8 T cells, unlike their naive precursors, are capable of rapidly producing high levels of cytokines, killing target cells, and proliferating into numerous secondary effectors immediately upon Ag encounter. This ready-to-respond state contributes to their superior ability to confer protective immunity, yet the underlying molecular basis remains unknown. In this study, we show that memory CD8 T cells have increased histone acetylation compared with naive CD8 T cells; however, those activated without CD4 T cell help ("unhelped") remain hypoacetylated and fail to develop into functional, protective memory. Treatment with a histone deacetylase inhibitor during activation results in increased histone acetylation in unhelped CD8 T cells and restores their ability to differentiate into functional memory cells capable of immediate cytokine production and providing protective immunity. These results demonstrate that CD4 T help-dependent chromatin remodeling provides a molecular basis for the enhanced responsiveness of memory CD8 T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI045025.

² Address correspondence and reprint requests to Dr. Hao Shen, Department of Microbiology, University of Pennsylvania School of Medicine, 303C Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 10104. E-mail address: hshen{at}mail.med.upenn.edu

³ Abbreviations used in this paper: CD8 T_M, memory CD8 T cell; AcH3, histone H3 acetylation; CD4 T_H, CD4 T cell help; ChIP, chromatin immunoprecipitation; GP, glycoprotein; HDAC, histone deacetylase; P+I, PMA and ionomycin; TSA, trichostatin A.

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