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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900592v1 183/3/1695    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Agarwal, P. Articles by Mescher, M. F. PubMed PubMed Citation Articles by Agarwal, P. Articles by Mescher, M. F.

Gene Regulation and Chromatin Remodeling by IL-12 and Type I IFN in Programming for CD8 T Cell Effector Function and Memory¹

Pujya Agarwal^*,, Arvind Raghavan^2,*,, Sarada L. Nandiwada^*,, Julie M. Curtsinger^*,, Paul R. Bohjanen^*,,, Daniel L. Mueller^*, and Matthew F. Mescher^3,*,

^* Center for Immunology and Departments of Laboratory Medicine and Pathology, Medicine, and Microbiology, University of Minnesota, Minneapolis, MN 55455

A third signal that can be provided by IL-12 or type I IFN is required for differentiation of naive CD8 T cells responding to Ag and costimulation. The cytokines program development of function and memory within 3 days of initial stimulation, and we show here that programming involves regulation of a common set of 355 genes including T-bet and eomesodermin. Much of the gene regulation program is initiated in response to Ag and costimulation within 24 h but is then extinguished unless a cytokine signal is available. Histone deacetylase inhibitors mimic the effects of IL-12 or type I IFN signaling, indicating that the cytokines relieve repression and allow continued gene expression by promoting increased histone acetylation. In support of this, increased association of acetylated histones with the promoter loci of granzyme B and eomesodermin is shown to occur in response to IL-12, IFN-, or histone deacetylase inhibitors. Thus, IL-12 and IFN-/β enforce in common a complex gene regulation program that involves, at least in part, chromatin remodeling to allow sustained expression of a large number of genes critical for CD8 T cell function and memory.

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 Grants R01 AI34824 (to M.F.M.), PO1 AI35296 (to M.F.M. and D.L.M.), and R01 GM54706 (to D.L.M.).

² Current address: Signum Biosciences, 7 Deer Park Drive, Monmouth Junction, NJ 08852.

³ Address correspondence and reprint requests to Dr. Matthew F. Mescher, Center for Immunology, 312 Church Street SE, Minneapolis, MN 55455. E-mail address: mesch001{at}umn.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; Ag-B7, Ag and B7-1 ligand; aAPC, artificial APC; LCMV, lymphocytic choriomeningitis virus; grzB, granzyme B; EST, expressed sequence tag; TSA, trichostatin A; VV, vaccinia virus; eomes, eomesodermin; WT, wild type; HDAC, histone deacetylase.

⁵ The on-line version of this article contains supplemental material.