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Blimp-1 Attenuates Th1 Differentiation by Repression of ifng, tbx21, and bcl6 Gene Expression

Luisa Cimmino^*, Gislaine A. Martins, Jerry Liao, Erna Magnusdottir, Gabriele Grunig, Rocio K. Perez and Kathryn L. Calame^1,*,

^* The Institute of Human Nutrition, Department of Microbiology, Department of Biological Sciences, and Department of Biochemistry and Molecular Biophysicis, College of Physicians and Surgeons, Columbia University, New York, NY 10032

T cell-specific deletion of Blimp-1 causes abnormal T cell homeostasis and function, leading to spontaneous, fatal colitis in mice. Herein we explore the role of Blimp-1 in Th1/Th2 differentiation. Blimp-1 mRNA and protein are more highly expressed in Th2 cells compared with Th1 cells, and Blimp-1 attenuates IFN- production in CD4 cells activated under nonpolarizing conditions. Although Blimp-1-deficient T cells differentiate normally to Th2 cytokines in vitro, Blimp-1 is required in vivo for normal Th2 humoral responses to NP-KLH (4-hydroxy-3-nitrophenylacetyl/keyhole lymphocyte hemocyanin) immunization. Lack of Blimp-1 in CD4 T cells causes increased IFN-, T-bet, and Bcl-6 mRNA. By chromatin immunoprecipitation we show that Blimp-1 binds directly to a distal regulatory region in the ifng gene and at multiple sites in tbx21 and bcl6 genes. Our data provide evidence that Blimp-1 functions in Th2 cells to reinforce Th2 differentiation by repressing critical Th1 genes.

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 Address correspondence and reprint requests to Dr. Kathryn Calame, Department of Biochemistry and Molecular Biophysicis, College of Physicians and Surgeons, Columbia University, 701 168th Street, Hammer Health Science Center 1202, Manhattan, NY 10032. E-mail address: KLC1{at}columbia.edu

² Abbreviations used in this paper: Blimp-1, B lymphocyte-induced maturation protein-1; Bcl-6, B cell lymphoma-6; ChIP, chromatin immunoprecipitation; CNS, conserved noncoding sequence; IP, immunoprecipitation; MFI, mean fluorescence intensity; NP-KLH, 4-hydroxy-3-nitrophenylacetyl/keyhole lymphocyte hemocyanin.

³ The online version of this article contains supplemental material.