Institut für Physiologische Chemie, Medizinische Fakultät Carl Gustav Carus, Technische Unversität Dresden, D-01307 Dresden, Germany; and.
Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021.
J Immunol. 2020 Sep 1;205(5):1306-1317. doi: 10.4049/jimmunol.2000020. Epub 2020 Jul 24.
Although GM-CSF has been widely used in dendritic cell (DC) research, the mechanisms, factors, and signals regulating steady-state differentiation and maturation of GM-CSF-dependent DCs are insufficiently known. We found that the absence, individually or combined, of the related proteins DEF6 and SWAP-70 strongly enhances differentiation of murine GM-CSF-derived DCs. Contrasting SWAP-70, control through DEF6 does not depend on RHOA activation. DEF6 deficiency leads to expression of the DC-specific transcription factor ZBTB46 and prolonged STAT5 activation in GM-CSF cultures. SWAP-70 and DEF6-mediated restriction of DC differentiation converges mechanistically at the NF-κB pathway. DEF6 acts at early stages of DC differentiation in CD115cKIT myeloid DC progenitors, whereas SWAP-70 acts subsequently. SWAP-70 and DEF6 regulate steady-state DC cytokine expression as well as in vivo accumulation in lymphatic tissue of migratory DCs. Our studies thus elucidate previously unknown roles of two closely related factors with distinct and complementary activities in DC differentiation and steady-state DC function.
虽然 GM-CSF 已被广泛应用于树突状细胞（DC）研究，但调节 GM-CSF 依赖性 DC 稳定分化和成熟的机制、因素和信号仍知之甚少。我们发现，相关蛋白 DEF6 和 SWAP-70 的缺失或组合缺失，均可显著增强鼠 GM-CSF 衍生的 DC 的分化。与 SWAP-70 相反，通过 DEF6 进行的调控不依赖于 RHOA 的激活。DEF6 缺陷导致 DC 特异性转录因子 ZBTB46 的表达，并延长 GM-CSF 培养物中 STAT5 的激活。SWAP-70 和 DEF6 介导的 DC 分化限制在 NF-κB 途径中具有机制上的一致性。DEF6 在 CD115cKIT 髓样 DC 祖细胞的 DC 分化早期阶段发挥作用，而 SWAP-70 随后发挥作用。SWAP-70 和 DEF6 调节稳态 DC 细胞因子表达以及体内迁移 DC 在淋巴组织中的积累。因此，我们的研究阐明了两个密切相关的因子在 DC 分化和稳态 DC 功能中的先前未知作用，它们具有独特且互补的活性。
