STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function
STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function
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DOI：
10.1038/s41423-020-00611-6
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发表时间：
2021-01
影响因子：
24.1
通讯作者：
Yongxia Wu;C. Tang;Corey Mealer;D. Bastian;M. Hanief Sofi;Linlu Tian;Steven Schutt;Hee-Jin Choi;Taylor Ticer;Mengmeng Zhang;Xiaohui Sui;Lei Huang;A. Mellor;C. Hu;Xue-Zhong Yu
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作者：
Yongxia Wu;C. Tang;Corey Mealer;D. Bastian;M. Hanief Sofi;Linlu Tian;Steven Schutt;Hee-Jin Choi;Taylor Ticer;Mengmeng Zhang;Xiaohui Sui;Lei Huang;A. Mellor;C. Hu;Xue-Zhong Yu
干扰素基因刺激因子（STING）介导的天然免疫激活在肿瘤和自身DNA诱导的抗肿瘤免疫和自身免疫中起关键作用。然而，STING也可以抑制肿瘤免疫和自身免疫。据报道，宿主非造血细胞中的STING信号传导可以防止或促进移植物抗宿主病（GVHD），这是同种异体造血细胞移植（allo-HCT）的主要并发症。宿主造血抗原提呈细胞（APC）在GVHD启动过程中对供者T细胞启动起关键作用。然而，STING如何在allo-HCT后调节宿主造血APC仍然未知。我们利用allo-HCT的鼠模型来评估STING在造血APC中的作用。STING缺陷的受者在主要组织相容性复合物错配的allo-HCT后发生更严重的GVHD。使用骨髓嵌合体，我们发现宿主造血细胞中的STING缺陷是导致疾病恶化的主要原因。此外，宿主CD 11 c+细胞上的STING在抑制同种异体T细胞应答中起主导作用。从机制上讲，STING缺陷导致APC（包括巨噬细胞和树突状细胞）的存活、活化和功能增加。一致地，STING的组成性活化减弱了从STING V154 M敲入小鼠分离的APC的存活、活化和功能。STING缺陷的APC增强了供体T细胞扩增、趋化因子受体表达和向肠组织中的迁移，导致加速/加重的GVHD。使用药理学方法，我们证明了在移植前向受体小鼠全身给予STING激动剂（双-（3′-5′）-环二聚鸟苷单磷酸）显著降低了GVHD死亡率。总之，我们揭示了STING在APC活性中的新作用，其决定T细胞同种异体应答，并验证了STING作为控制allo-HCT后GVHD的潜在治疗靶点。
Stimulator of interferon genes (STING)-mediated innate immune activation plays a key role in tumor- and self-DNA-elicited antitumor immunity and autoimmunity. However, STING can also suppress tumor immunity and autoimmunity. STING signaling in host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic cell transplantation (allo-HCT). Host hematopoietic antigen-presenting cells (APCs) play key roles in donor T-cell priming during GVHD initiation. However, how STING regulates host hematopoietic APCs after allo-HCT remains unknown. We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs. STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT. Using bone marrow chimeras, we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease. Furthermore, STING on host CD11c+cells played a dominant role in suppressing allogeneic T-cell responses. Mechanistically, STING deficiency resulted in increased survival, activation, and function of APCs, including macrophages and dendritic cells. Consistently, constitutive activation of STING attenuated the survival, activation, and function of APCs isolated from STING V154M knock-in mice. STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression, and migration into intestinal tissues, resulting in accelerated/exacerbated GVHD. Using pharmacologic approaches, we demonstrated that systemic administration of a STING agonist (bis-(3′-5′)-cyclic dimeric guanosine monophosphate) to recipient mice before transplantation significantly reduced GVHD mortality. In conclusion, we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.