Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD
Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD
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DOI：
10.1182/blood-2013-05-500876
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发表时间：
2014-09-18
期刊：
影响因子：
20.3
通讯作者：
Fry, Terry J.
中科院分区：
文献类型：
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作者：
Capitini, Christian M.;Nasholm, Nicole M.;Fry, Terry J.
选择性靶向非t细胞，包括抗原提呈细胞（APCs），是预防移植物抗宿主病（GVHD）但维持移植物抗肿瘤（GVT）效应的潜在策略。由于I型和II型干扰素通过信号换能器和转录激活因子1 （STAT1）发出信号，并有助于异体骨髓移植（alloBMT）后APCs的激活，我们研究了供体APCs中STAT1的缺失是否可以在保持免疫能力的同时预防GVHD。移植STAT1（-/-）骨髓（BM）可阻止STAT1(+/+) T细胞诱导的GVHD，导致B220（+）细胞和调节性T细胞扩增。STAT1(-/-) BM还能保持GVT活性，提高GVHD环境下肿瘤攻击小鼠的总存活率。此外，同种异体STAT1（-/-）骨髓移植的受体显示出CD9(-) Siglec H浆细胞样树突状细胞（pDCs）的增加，并且STAT1（-/-）骨髓移植后pDCs的消耗阻止了GVHD的抵抗。发现STAT1(-/-) pDCs产生自由基，IFN α和白细胞介素(IL)-12减少，IL-10增加。此外，同种异体骨髓移植后分离的STAT1(-/-) pDCs显示S100A8和S100A9基因表达增加，S100A9（-/-）骨髓移植降低了无gvhd存活。最后，在同种异体bmt后分离的STAT1(-/-) pDCs中发现STAT3升高。我们的结论是，干扰干扰素信号在apc如pDCs提供了一种新的方法来调节GVHD/GVT轴。
Selective targeting of non-T cells, including antigen-presenting cells (APCs), is a potential strategy to prevent graft-versus-host-disease (GVHD) but to maintain graft-versus-tumor (GVT) effects. Because type I and II interferons signal through signal transducer and activator of transcription-1 (STAT1), and contribute to activation of APCs after allogeneic bone marrow transplant (alloBMT), we examined whether the absence of STAT1 in donor APCs could prevent GVHD while preserving immune competence. Transplantation of STAT1(-/-) bone marrow (BM) prevented GVHD induced by STAT1(+/+) T cells, leading to expansion of B220(+) cells and regulatory T cells. STAT1(-/-) BM also preserved GVT activity and enhanced overall survival of tumor-challenged mice in the setting of GVHD. Furthermore, recipients of allogeneic STAT1(-/-) BM demonstrated increased CD9(-) Siglec H hi plasmacytoid dendritic cells (pDCs), and depletion of pDCs after STAT1(-/-) BM transplantation prevented GVHD resistance. STAT1(-/-) pDCs were found to produce decreased free radicals, IFN alpha, and interleukin (IL)-12, and increased IL-10. Additionally, STAT1(-/-) pDCs that were isolated after alloBMT showed increased gene expression of S100A8 and S100A9, and transplantation of S100A9(-/-) BM reduced GVHD-free survival. Finally, elevated STAT3 was found in STAT1(-/-) pDCs isolated after alloBMT. We conclude that interfering with interferon signaling in APCs such as pDCs provides a novel approach to regulate the GVHD/GVT axis.