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Notch Regulates Cytolytic Effector Function in CD8⁺ T Cells¹

Ok Hyun Cho^*, Hyun Mu Shin, Lucio Miele, Todd E. Golde, Abdul Fauq, Lisa M. Minter^* and Barbara A. Osborne^2,*,

^* Department of Veterinary and Animal Sciences, and Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003; Breast Cancer Research Program, Cardinal Bernadin Cancer Center, Loyola University, Maywood, IL 60153; and Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224

The maturation of naive CD8⁺ T cells into effector CTLs is a critical feature of a functional adaptive immune system. Development of CTLs depends, in part, upon the expression of the transcriptional regulator eomesodermin (EOMES), which is thought to regulate expression of two key effector molecules, perforin and granzyme B. Although EOMES is important for effector CTL development, the precise mechanisms regulating CD8⁺ effector cell maturation remains poorly understood. In this study, we show that Notch1 regulates the expression of EOMES, perforin, and granzyme B through direct binding to the promoters of these crucial effector molecules. By abrogating Notch signaling, both biochemically as well as genetically, we conclude that Notch activity mediates CTL activity through direct regulation of EOMES, perforin, and granzyme B.

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 Grants RO1 AI049361 and PO1 AG 025531 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Barbara A. Osborne, Department of Veterinary & Animal Sciences, 311 Paige Lab 161 Holdsworth Way, University of Massachusetts, Amherst, MA 01003. E-mail address: osborne{at}vasci.umass.edu

³ Abbreviations used in this paper: FasL, Fas ligand; EOMES, eomesodermin; GSI, gamma-secretase inhibitor; AS, antisense; ChIP, chromatin immunoprecipitation.

⁴ The online version of this article contains supplemental material.