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high and IL-7Rlow CD8 T Cells during Infection Is Regulated by the Opposing Functions of GABP and Gfi-11
* Department of Immunobiology, Yale Medical School, New Haven, CT 06511; and
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases and
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892
IL-7 is essential for the survival of naive and memory T cells, and IL-7 receptor 
-chain (IL-7R) expression is dynamically regulated in activated CD8 T cells during acute viral and bacterial infections. Most virus-specific CD8 T cells become IL-7Rlow and are relatively short-lived, but some escape IL-7R repression (referred to as IL-7Rhigh memory precursor effector cells) and preferentially enter the memory CD8 T cell pool. How antiviral effector CD8 T cells regulate IL-7R expression in an "on and off" fashion remains to be characterized. During lymphocytic choriomeningitis virus infection, we found that opposing actions of the transcription factors GABP (GA binding protein ) and Gfi-1 (growth factor independence 1) control IL-7R expression in effector CD8 T cells. Specifically, GABP was required for IL-7R expression in memory precursor effector cells, and this correlated with hyperacetylation of the Il7ra promoter. In contrast, Gfi-1 was required for stable IL-7R repression in effector CD8 T cells and acted by antagonizing GABP binding and recruiting histone deacetylase 1, which deacetylated the Il7ra promoter. Thus, Il7ra promoter acetylation and activity was dependent on the reciprocal binding of GABP and Gfi-1, and these data provide a biochemical mechanism for the generation of stable IL-7Rhigh and IL-7Rlow states in virus-specific effector 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 the Burroughs-Wellcome Fund 1004313 (to S.M.K.), National Institutes of Health Grant R01 AI 066232-01 (to S.M.K.), Edward Mallinckrodt, Jr., Foundation (to S.M.K.), and intramural research support from the National Institute of Allergy and Infectious Diseases (to W.E.P. and J.Z.) and the National Heart, Lung and Blood Institute, National Institutes of Health (to W.J.L.).
2 Address correspondence and reprint requests to Dr. Susan M Kaech, Department of Immunobiology, Yale Medical School, The Anlyan Center S640, 300 Cedar Street, New Haven, CT 06511. E-mail address: Susan.Kaech{at}yale.edu
3 Abbreviations used in this paper: 
c, common cytokine receptor -chain; ChIP, chromatin immunoprecipitation; ECR, evolutionary conserved region; GABP, GA binding protein ; Gfi-1, growth factor independence 1; HDAC, histone deacetylase; H3K9, histone 3 acetylated at lysine 9; LCMV, lymphocytic choriomeningitis virus; MFI, mean fluorescence intensity; MPEC, memory precursor effector cell; p.i., postinfection; qRT-PCR, quantitative real-time PCR; RV, retrovirus; shGabp, Gabp knocked down by short hairpin RNA interference; SLEC, short-lived effector cell; tg, transgenic; TSA, trichostatin A; RNAi, RNA interference.
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