Woods David M, Woan Karrune V, Cheng Fengdong, Sodré Andressa L, Wang Dapeng, Wu Yongxia, Wang Zi, Chen Jie, Powers John, Pinilla-Ibarz Javier, Yu Yu, Zhang Ya, Wu Xuefeng, Zheng Xiaoyan, Weber Jeffrey, Hancock Wayne W, Seto Edward, Villagra Alejandro, Yu Xue-Zhong, Sotomayor Eduardo M
H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY.
Blood. 2017 Jul 13;130(2):146-155. doi: 10.1182/blood-2016-08-731505. Epub 2017 May 26.
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 and (, transcription factors previously shown to regulate inflammatory cytokine and effector molecule production. Conversely, overexpression of HDAC11 resulted in decreased expression of these genes. Chromatin immunoprecipitation showed the presence of HDAC11 at the and gene promoters in resting T cells, where it rapidly disassociated following T-cell activation. In vivo, HDAC11KO T cells were refractory to tolerance induction. HDAC11KO T 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-γ, 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.
组蛋白乙酰化以及负责控制这些表观遗传标记的酶家族与调节T细胞成熟和表型有关。在此，我们证明了组蛋白去乙酰化酶11（HDAC11）在调节T细胞效应功能方面具有先前未明确的作用。使用EGFP - HDAC11转基因报告小鼠，我们发现相对于幼稚和中枢记忆T细胞群体，效应T细胞中HDAC11的表达较低，静息T细胞的激活导致其表达降低。使用HDAC11基因敲除（KO）小鼠进行的实验表明，这些小鼠的T细胞表现出增强的增殖、促炎细胞因子产生和效应分子表达。此外，HDAC11基因敲除的T细胞中 和 （先前已证明可调节炎性细胞因子和效应分子产生的转录因子）的表达增加。相反，HDAC11的过表达导致这些基因的表达降低。染色质免疫沉淀显示在静息T细胞的 和 基因启动子处存在HDAC11，在T细胞激活后它会迅速解离。在体内，HDAC11基因敲除的T细胞对耐受诱导具有抗性。HDAC11基因敲除的T细胞在小鼠模型中还介导了急性移植物抗宿主病（GVHD）的加速发作，其特征是T细胞增殖增加以及干扰素 - γ、肿瘤坏死因子和EOMES的表达增加。此外，在小鼠B细胞淋巴瘤模型中，HDAC11基因敲除的T细胞的过继转移导致肿瘤负担显著降低。综上所述，这些数据证明了HDAC11作为T细胞效应表型和功能的负性表观遗传调节因子的先前未知作用。
