STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets
STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets
复制标题
STING对CD8与CD4 T细胞亚群介导的实验性GVHD有差异调节
DOI：
10.1126/scitranslmed.aay5006
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发表时间：
2020-07-15
影响因子：
17.1
通讯作者：
Levy, Robert B.
中科院分区：
文献类型：
--
作者：
Bader, Cameron S.;Barreras, Henry;Levy, Robert B.
干扰素基因刺激剂（STING）通路被认为是胃肠道稳态和炎症反应的关键调节因子。据报道，尽管 STING 可在主要组织相容性复合物 (MHC) 不匹配的同种异体造血干细胞移植 (aHSCT) 后预防肠道屏障损伤和移植物抗宿主病 (GVHD)，但其在临床相关 MHC 匹配的 aHSCT 中的作用尚不清楚。研究表明，非造血细胞中的 STING 信号传导促进了 MHC 匹配的 aHSCT 诱导的 GVHD，并且 STING 激动剂增加了非造血小鼠肠道类器官培养物中 I 型干扰素和 MHC I 的表达。此外，表达含有与STING活性降低相关的三个单核苷酸多态性的人类STING等位基因的小鼠也出现MHC匹配GVHD降低，这证明了STING潜在的临床重要性。在 MHC 匹配和 MHC 不匹配模型中移植纯化的供体 CD8+ T 细胞后，STING(-/-) 受者的 GVHD 降低，这使看似不同的结果得到了一致。进一步检查发现，STING 缺陷减少了移植后早期供体 CD8(+) T 细胞的活化，并促进了受体 MHC II+ 抗原呈递细胞 (APC) 的存活。因此，STING通路缺失中APC的持续存在可能是完全不匹配的受体中CD4+T细胞介导的GVHD增加的原因。总的来说，我们的研究结果对于通过 aHSCT 后早期靶向 STING 来调节临床 GVHD 具有重要意义，并证明先天免疫途径对 aHSCT 的结果具有相反的影响，具体取决于供体/受体的 MHC 差异。
The stimulator of interferon genes (STING) pathway has been proposed as a key regulator of gastrointestinal homeostasis and inflammatory responses. Although STING reportedly protects against gut barrier damage and graft-versus-host disease (GVHD) after major histocompatibility complex (MHC)-mismatched allogeneic hematopoietic stem cell transplantation (aHSCT), its effect in clinically relevant MHC-matched aHSCT is unknown. Studies here demonstrate that STING signaling in nonhematopoietic cells promoted MHC-matched aHSCT-induced GVHD and that STING agonists increased type I interferon and MHC I expression in nonhematopoietic mouse intestinal organoid cultures. Moreover, mice expressing a human STING allele containing three single-nucleotide polymorphisms associated with decreased STING activity also developed reduced MHC-matched GVHD, demonstrating STING's potential clinical importance. STING(-/-) recipients experienced reduced GVHD with transplant of purified donor CD8(+) T cells in both MHC-matched and MHC-mismatched models, reconciling the seemingly disparate results. Further examination revealed that STING deficiency reduced the activation of donor CD8(+) T cells early after transplant and promoted recipient MHC class II+ antigen-presenting cell (APC) survival. Therefore, APC persistence in STING pathway absence may account for the increased GVHD mediated by CD4(+) T cells in completely mismatched recipients. In total, our findings have important implications for regulating clinical GVHD by targeting STING early after aHSCT and demonstrate that an innate immune pathway has opposing effects on the outcome of aHSCT, depending on the donor/recipient MHC disparity.