Discovery Research, Cancer Immunology & Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Discovery Research, Structural Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Immunohorizons. 2023 Mar 1;7(3):200-212. doi: 10.4049/immunohorizons.2200072.
Regulatory T cells (Treg) play a critical role in controlling immune responses in diseases such as cancer or autoimmunity. Activated Treg express the membrane protein GARP (LRRC32) in complex with the latent form of the immunosuppressive cytokine TGF-β (L-TGF-β). In this study, we confirmed that active TGF-β was generated from its latent form in an integrin-dependent manner and induced TGF-β receptor signaling in activated human Treg. We studied a series of Abs targeting the L-TGF-β/GARP complex with distinct binding modes. We found that TGF-β receptor signaling could be inhibited by anti-TGF-β and by some, but not all, Abs against the L-TGF-β/GARP complex. Cryogenic electron microscopy structures of three L-TGF-β/GARP complex-targeting Abs revealed their distinct epitopes and allowed us to elucidate how they achieve blockade of TGF-β activation. Three different modes of action were identified, including a novel unusual mechanism of a GARP-binding Ab. However, blockade of GARP or TGF-β by Abs did not influence the suppressive activity of human Treg in vitro. We were also not able to confirm a prominent role of GARP in other functions of human Treg, such as FOXP3 induction and Treg stability. These data show that the GARP/TGF-β axis can be targeted pharmacologically in different ways, but further studies are necessary to understand its complexity and to unleash its therapeutic potential.
调节性 T 细胞（Treg）在控制癌症或自身免疫等疾病的免疫反应中起着关键作用。活化的 Treg 表达膜蛋白 GARP（LRRC32），与免疫抑制细胞因子 TGF-β 的潜伏形式（L-TGF-β）形成复合物。在这项研究中，我们证实 TGF-β 以整合素依赖的方式从其潜伏形式中产生，并在活化的人 Treg 中诱导 TGF-β 受体信号。我们研究了一系列针对 L-TGF-β/GARP 复合物的具有不同结合模式的 Ab。我们发现 TGF-β 受体信号可以被抗 TGF-β 和一些但不是所有针对 L-TGF-β/GARP 复合物的 Ab 抑制。三种靶向 L-TGF-β/GARP 复合物的 Ab 的低温电子显微镜结构揭示了它们不同的表位，并使我们能够阐明它们如何实现 TGF-β 激活的阻断。确定了三种不同的作用模式，包括一种 GARP 结合 Ab 的新型不寻常机制。然而，Ab 阻断 GARP 或 TGF-β 并不影响人 Treg 在体外的抑制活性。我们也无法证实 GARP 在人 Treg 的其他功能（如 FOXP3 诱导和 Treg 稳定性）中起主要作用。这些数据表明，GARP/TGF-β 轴可以以不同的方式进行药理学靶向，但需要进一步研究来了解其复杂性并释放其治疗潜力。
