人体在受病原微生物感染时，淋巴系统的CD4+T细胞可被细胞因子白介素-12诱导向Th1细胞定向分化并分泌干扰素IFNg。Th1细胞和巨噬细胞参与机体免疫应答以便清除病原菌。申请人在研究Th1分化机理时发现，去乙酰转移酶HDAC6的特异性抑制剂能够显著地促进Th1细胞分化，并且T细胞中HDAC6与STAT4相互作用。STAT4是促进Th1分化的重要转录因子，申请人推测：STAT4依赖乙酰化修饰而激活诱导Th1定向分化，而HDAC6通过去乙酰化STAT4而抑制Th1细胞分化，故靶向HDAC6可以增强Th1抗菌能力，克服传统病原微生物感染治疗面对的抗生素耐药性问题。我们将研究：1)分析STAT4乙酰化修饰调控Th1细胞分化的机理；2)阐明HDAC6去乙酰化对Th1分化的抑制；3)探索靶向抑制HDAC6在微生物感染疾病的治疗作用。本项目的实施将对克服病原菌感染抗生素治疗耐药性提供思路和方法。

Upon intracellular pathogen infection against host, interleukin-12 in the microenvironment induce STAT4 activation, which is essential for T helper type 1 (Th1) cell differentiation and secretion of IFNg. Th1 and macrophage are involved in the immune response to help the host to clear the pathogen. Post-translational modifications on STAT4 are critical for its activity. In this project, we initially found that the selective inhibitory compounds of HDAC6 enhanced Th1 cell differentiation substantially. Meanwhile, HDAC6 could interact with STAT4 in T cells. We hypothesized that HDAC6 inhibited Th1 cell differentiation via deacetylating STAT4. We will further investigate the regulatory effect of HDAC6 on Th1 cell differentiation, verify how acetylation on STAT4 affect its function, analyze how HDAC6 deacetylate STAT4, and illustrate the physiological role of STAT4 acetylation on Th1 cell differentiation. At the end of the project, the selective HDAC6 inhibitors’ potential effect of promoting the anti-intracellular bacterial function of Th1 cells will be explored. Taken together, this study will accomplish the molecular mechanism of how STAT4 acetylation regulate Th1 cell differentiation and highlight the therapeutic potential of HDAC6 inhibitors for controlling intracellular pathogen infections.