Institute of Molecular Health Sciences, ETH Zurich, Zürich, Switzerland.
Department of BioMedical Research, University of Bern, Department of Immunology RIA, University Hospital Bern, Bern, Switzerland.
Eur J Immunol. 2019 May;49(5):709-723. doi: 10.1002/eji.201848044. Epub 2019 Mar 1.
Antioxidant systems maintain cellular redox homeostasis. The thioredoxin-1 (Trx1) and the glutathione (GSH)/glutaredoxin-1 (Grx1) systems are key players in preserving cytosolic redox balance. In fact, T lymphocytes critically rely on reducing equivalents from the Trx1 system for DNA biosynthesis during metabolic reprogramming upon activation. We here show that the Trx1 system is also indispensable for development and functionality of marginal zone (MZ) B cells and B1 cells in mice. In contrast, development of conventional B cells, follicular B-cell homeostasis, germinal center reactions, and antibody responses are redundantly sustained by both antioxidant pathways. Proliferating B2 cells lacking Txnrd1 have increased glutathione (GSH) levels and upregulated cytosolic Grx1, which is barely detectable in expanding thymocytes. These results suggest that the redox capacity driving proliferation is more robust and flexible in B cells than in T cells, which may have profound implications for the therapy of B and T-cell neoplasms.
抗氧化系统维持细胞的氧化还原稳态。硫氧还蛋白-1（Trx1）和谷胱甘肽（GSH）/谷胱甘肽还原酶-1（Grx1）系统是维持细胞浆氧化还原平衡的关键因素。事实上，T 淋巴细胞在激活时通过代谢重编程进行 DNA 生物合成时，严重依赖于 Trx1 系统提供的还原当量。我们在这里表明，Trx1 系统对于小鼠边缘区（MZ）B 细胞和 B1 细胞的发育和功能也是必不可少的。相比之下，传统 B 细胞的发育、滤泡 B 细胞的稳态、生发中心反应和抗体反应都可以由这两种抗氧化途径冗余地维持。增殖的 B2 细胞缺乏 Txnrd1 时，其谷胱甘肽（GSH）水平升高，细胞质 Grx1 上调，而在扩增的胸腺细胞中几乎检测不到 Grx1。这些结果表明，驱动增殖的氧化还原能力在 B 细胞中比在 T 细胞中更强大且灵活，这可能对 B 和 T 细胞肿瘤的治疗具有深远的影响。
