Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland.
Eur J Immunol. 2021 Jan;51(1):115-124. doi: 10.1002/eji.202048851. Epub 2020 Sep 28.
Thioredoxin-1 (Trx1) is a vital component for cellular redox homeostasis. In T cells, Trx1 donates electrons for the de novo synthesis of deoxyribonucleotides to allow rapid cell proliferation. The Trx-interacting protein (Txnip) binds to the reduced Trx1 and inhibits its activity. However, the role of Txnip in adaptive immunity in vivo is unknown. Here, we show that absence of Txnip increased proliferation of effector T cells and GC B-cell responses in response to lymphocytic choriomeningitis virus and Qβ virus-like particles, respectively, but did not affect development and homeostasis of T and B cells. While downregulation of Txnip and concomitant upregulation of Trx1 is critical for rapid T-cell expansion upon viral infection, re-expression of Txnip and consequently inhibition of Trx1 is important to restrain late T-cell expansion. Importantly, we demonstrated that T-cell receptor (TCR) engagement but not CD28 costimulation is critically required for Txnip downregulation. Thus, this study further uncovers positive and negative control of lymphocyte proliferation by the Trx1 system.
硫氧还蛋白 1（Trx1）是细胞氧化还原稳态的重要组成部分。在 T 细胞中，Trx1 为脱氧核苷酸的从头合成提供电子，以允许快速细胞增殖。硫氧还蛋白相互作用蛋白（Txnip）与还原型 Trx1 结合并抑制其活性。然而，Txnip 在体内适应性免疫中的作用尚不清楚。在这里，我们表明 Txnip 的缺失增加了效应 T 细胞的增殖和 GC B 细胞对淋巴细胞性脉络丛脑膜炎病毒和 Qβ 病毒样颗粒的反应，而不影响 T 和 B 细胞的发育和稳态。虽然 Txnip 的下调和随之而来的 Trx1 的上调对于病毒感染后 T 细胞的快速扩增至关重要，但 Txnip 的重新表达和 Trx1 的抑制对于抑制晚期 T 细胞扩增很重要。重要的是，我们证明 TCR 结合但不是 CD28 共刺激对于 Txnip 的下调是至关重要的。因此，本研究进一步揭示了 Trx1 系统对淋巴细胞增殖的正调控和负调控。
