Velaga Sarvari, Ukena Sya N, Dringenberg Ulrike, Alter Christina, Pardo Julian, Kershaw Olivia, Franzke Anke
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Immune Effector Cells Group (ICE), Biomedical Research Centre of Aragon (CIBA), Zaragoza, Spain.
PLoS One. 2015 Apr 30;10(4):e0124927. doi: 10.1371/journal.pone.0124927. eCollection 2015.
In our previous work we could identify defects in human regulatory T cells (Tregs) likely favoring the development of graft-versus-host disease (GvHD) following allogeneic stem cell transplantation (SCT). Treg transcriptome analyses comparing GvHD and immune tolerant patients uncovered regulated gene transcripts highly relevant for Treg cell function. Moreover, granzyme A (GZMA) also showed a significant lower expression at the protein level in Tregs of GvHD patients. GZMA induces cytolysis in a perforin-dependent, FAS-FASL independent manner and represents a cell-contact dependent mechanism for Tregs to control immune responses. We therefore analyzed the functional role of GZMA in a murine standard model for GvHD. For this purpose, adoptively transferred CD4+CD25+ Tregs from gzmA-/- mice were analyzed in comparison to their wild type counterparts for their capability to prevent murine GvHD. GzmA-/- Tregs home efficiently to secondary lymphoid organs and do not show phenotypic alterations with respect to activation and migration properties to inflammatory sites. Whereas gzmA-/- Tregs are highly suppressive in vitro, Tregs require GZMA to rescue hosts from murine GvHD, especially regarding gastrointestinal target organ damage. We herewith identify GZMA as critical effector molecule of human Treg function for gastrointestinal immune response in an experimental GvHD model.
在我们之前的研究中，我们能够确定人类调节性T细胞（Tregs）中的缺陷，这些缺陷可能有利于异基因干细胞移植（SCT）后移植物抗宿主病（GvHD）的发展。对GvHD患者和免疫耐受患者的Treg转录组分析发现了与Treg细胞功能高度相关的调控基因转录本。此外，颗粒酶A（GZMA）在GvHD患者Tregs中的蛋白水平也显著降低。GZMA以穿孔素依赖、FAS - FASL非依赖的方式诱导细胞溶解，代表了Tregs控制免疫反应的细胞接触依赖机制。因此，我们在GvHD的小鼠标准模型中分析了GZMA的功能作用。为此，将来自gzmA - / -小鼠的过继转移CD4 + CD25 + Tregs与其野生型对应物进行比较，分析它们预防小鼠GvHD的能力。gzmA - / - Tregs能有效地归巢到次级淋巴器官，并且在激活和向炎症部位迁移特性方面未表现出表型改变。虽然gzmA - / - Tregs在体外具有高度抑制作用，但Tregs需要GZMA来拯救宿主免受小鼠GvHD的影响，尤其是在胃肠道靶器官损伤方面。我们在此确定GZMA是实验性GvHD模型中人类Treg功能对胃肠道免疫反应的关键效应分子。
