Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Cell Rep. 2023 Mar 28;42(3):112250. doi: 10.1016/j.celrep.2023.112250. Epub 2023 Mar 15.
Abundant donor cytotoxic T cells that attack normal host organs remain a major problem for patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). Despite an increase in our knowledge of the pathobiology of acute graft versus host disease (aGvHD), the mechanisms regulating the proliferation and function of donor T cells remain unclear. Here, we show that activated donor T cells express galectin-3 (Gal-3) after allo-HCT. In both major and minor histocompatibility-mismatched models of murine aGvHD, expression of Gal-3 is associated with decreased T cell activation and suppression of the secretion of effector cytokines, including IFN-γ and GM-CSF. Mechanistically, Gal-3 results in activation of NFAT signaling, which can induce T cell exhaustion. Gal-3 overexpression in human T cells prevents severe disease by suppressing cytotoxic T cells in xenogeneic aGvHD models. Together, these data identify the Gal-3-dependent regulatory pathway in donor T cells as a critical component of inflammation in aGvHD.
在接受异基因造血细胞移植（allo-HCT）的患者中，攻击正常宿主器官的大量供体细胞毒性 T 细胞仍然是一个主要问题。尽管我们对急性移植物抗宿主病（aGvHD）的病理生物学有了更多的了解，但调节供体 T 细胞增殖和功能的机制仍不清楚。在这里，我们表明，激活的供体 T 细胞在 allo-HCT 后表达半乳糖凝集素-3（Gal-3）。在小鼠 aGvHD 的主要和次要组织相容性不匹配模型中，Gal-3 的表达与 T 细胞活化减少和效应细胞因子（包括 IFN-γ 和 GM-CSF）分泌的抑制有关。从机制上讲，Gal-3 导致 NFAT 信号的激活，从而诱导 T 细胞耗竭。Gal-3 在人 T 细胞中的过表达通过抑制异种移植物抗宿主病模型中的细胞毒性 T 细胞来预防严重疾病。总之，这些数据确定了供体 T 细胞中 Gal-3 依赖性调节途径是 aGvHD 炎症的一个关键组成部分。
