1. T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model.
- Author
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Woods, David M., Woan, Karrune V., Fengdong Cheng, Sodré, Andressa L., Dapeng Wang, Yongxia Wu, Zi Wang, Jie Chen, Powers, John, Pinilla-Ibarz, Javier, Yu Yu, Ya Zhang, Xuefeng Wu, Xiaoyan Zheng, Weber, Jeffrey, Hancock, Wayne W., Seto, Edward, Villagra, Alejandro, Xue-Zhong Yu, and Sotomayor, Eduardo M.
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MOUSE leukemia , *T cells , *HISTONE acetylation , *ENZYMES , *PHENOTYPES , *HISTONE deacetylase , *CYTOKINES , *CHROMATIN - Abstract
Histone acetylation and the families of enzymes responsible for controlling these epigenetic marks have been implicated in regulating T-cell maturation and phenotype. Here, we demonstrate a previously undefined role of histone deacetylase 11 (HDAC11) in regulating T-cell effector functions. Using EGFP-HDAC11 transgenic reporter mice, we found that HDAC11 expression was lower in effector relative to naive and central memory T-cell populations, and activation of resting T cells resulted in its decreased expression. Experiments using HDAC11 knockout (KO) mice revealed that T cells from these mice displayed enhanced proliferation, proinflammatory cytokine production, and effector molecule expression. In addition, HDAC11KO T cells had increased expression of Eomesodermin (Eomes) and TBX21 (Tbet), transcription factors previously shown to regulate inflammatory cytokine and effector molecule production. Conversely, over-expression of HDAC11 resulted in decreased expression of these genes. Chromatin immunoprecipitation showed the presence of HDAC11 at the Eomes and Tbet gene promoters in resting T cells, where it rapidly disassociated following T-cell activation. In vivo, HDAC11KO T cells were refractory to tolerance induction.HDAC11KOT cells also mediated accelerated onset of acute graft-versus-host disease (GVHD) in a murine model, characterized by increased proliferation of T cells and expression of interferon-g, tumor necrosis factor, and EOMES. In addition, adoptive transfer of HDAC11KO T cells resulted in significantly reduced tumor burden in a murine B-cell lymphoma model. Taken together, these data demonstrate a previously unknown role of HDAC11 as a negative epigenetic regulator of T-cell effector phenotype and function. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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