Georgiev Peter, Wang Yun, Muise Eric S, Bandi Madhavi L, Blumenschein Wendy, Sathe Manjiri, Pinheiro Elaine M, Shumway Stuart D
Merck & Co., Inc., Kenilworth, NJ 07033
Merck & Co., Inc., Kenilworth, NJ 07033.
Immunohorizons. 2019 Jul 11;3(7):294-305. doi: 10.4049/immunohorizons.1900037.
Bromodomain and extraterminal domain (BET) proteins help direct the differentiation of helper T cell subsets, but their role in activated T cell function has not been described in detail. In this study, we investigate various consequences of epigenetic perturbation in human T lymphocytes using MK-8628, a potent and highly selective inhibitor of BET proteins. MK-8628 reduces the expression of canonical transcripts directing the proliferation, activation, and effector function of T lymphocytes. Treatment with MK-8628 abolishes the expression of key cyclins required for cell cycle progression and induces G1 cell cycle arrest in TCR-activated lymphocytes. This antiproliferative phenotype partially results from T lymphocyte apoptosis, which is exacerbated by MK-8628. In naive and memory T cell subsets, MK-8628 antagonizes T cell activation and suppresses polyfunctional cytokine production. Collectively, our results describe potent immunosuppressive effects of BET inhibition on human T cell biology. These results have important implications for immune modulatory targeting of BET proteins in the settings of T cell-driven autoimmune inflammation.
溴结构域和额外末端结构域（BET）蛋白有助于指导辅助性T细胞亚群的分化，但其在活化T细胞功能中的作用尚未得到详细描述。在本研究中，我们使用MK-8628（一种强效且高度选择性的BET蛋白抑制剂）研究了人类T淋巴细胞中表观遗传扰动的各种后果。MK-8628降低了指导T淋巴细胞增殖、活化和效应功能的典型转录本的表达。用MK-8628处理可消除细胞周期进程所需关键细胞周期蛋白的表达，并在TCR活化的淋巴细胞中诱导G1期细胞周期停滞。这种抗增殖表型部分源于T淋巴细胞凋亡，而MK-8628会加剧这种凋亡。在初始和记忆T细胞亚群中，MK-8628拮抗T细胞活化并抑制多功能细胞因子的产生。总体而言，我们的结果描述了BET抑制对人类T细胞生物学的强效免疫抑制作用。这些结果对于在T细胞驱动的自身免疫性炎症背景下对BET蛋白进行免疫调节靶向具有重要意义。
