Indiana University School of Medicine, Indianapolis, IN 46202.
Indiana University School of Medicine, Indianapolis, IN 46202
J Immunol. 2019 May 15;202(10):3053-3064. doi: 10.4049/jimmunol.1800447. Epub 2019 Apr 12.
Acute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (HCT). Plasma levels of soluble membrane-bound ST2 (ST2) are elevated in human and murine aGVHD and correlated to type 1 T cells response. ST2 signals through the adapter protein MyD88. The role of MyD88 in T cells during aGVHD has yet to be elucidated. We found that knocking out MyD88 in the donor T cells protected against aGVHD independent of IL-1R and TLR4 signaling in two murine HCT models. This protection was entirely driven by MyD88 CD4 T cells. Transplanting donor MyD88 conventional T cells (Tcons) with wild-type (WT) or MyD88 regulatory T cells (Tregs) lowered aGVHD severity and mortality. Transcriptome analysis of sorted MyD88 CD4 T cells from the intestine 10 d post-HCT showed lower levels of (gene of ST2), , , , and Transplanting donor ST2 Tcons with WT or ST2 Tregs showed a similar phenotype with what we observed when using donor MyD88 Tcons. Decreased ST2 was confirmed at the protein level with less secretion of soluble ST2 and more expression of ST2 compared with WT T cells. Our data suggest that Treg suppression from lack of MyD88 signaling in donor Tcons during alloreactivity uses the ST2 but not the IL-1R or TLR4 pathways, and ST2 represents a potential aGVHD therapeutic target sparing Tregs.
急性移植物抗宿主病（aGVHD）会影响异基因造血细胞移植（HCT）的疗效。在人类和鼠类的 aGVHD 中，可检测到可溶性膜结合 ST2（ST2）的血浆水平升高，且与 1 型 T 细胞反应相关。ST2 通过衔接蛋白 MyD88 发出信号。MyD88 在 aGVHD 期间对 T 细胞的作用尚未阐明。我们发现，在两种小鼠 HCT 模型中，敲除供体 T 细胞中的 MyD88 可预防 aGVHD，且不依赖于 IL-1R 和 TLR4 信号。这种保护完全由 MyD88 CD4 T 细胞驱动。移植供体 MyD88 常规 T 细胞（Tcons）和野生型（WT）或 MyD88 调节性 T 细胞（Tregs）可降低 aGVHD 的严重程度和死亡率。HCT 后 10d 对分选的 MyD88 CD4 T 细胞进行转录组分析显示， （ST2 的基因）、 、 、 、 和 的水平较低。移植供体 ST2 Tcons 和 WT 或 ST2 Tregs 显示出与我们观察到的使用供体 MyD88 Tcons 时相似的表型。与 WT T 细胞相比，可溶性 ST2 的分泌减少，ST2 的表达增加，在蛋白质水平上证实了 ST2 降低。我们的数据表明，在同种异体反应期间，由于供体 Tcons 中缺乏 MyD88 信号，Treg 的抑制作用利用了 ST2 途径，而不是 IL-1R 或 TLR4 途径，ST2 是一种潜在的 aGVHD 治疗靶点，可保留 Treg。
