HTLV-1 infected T cells cause bone loss via small extracellular vesicles

IF 15.5 1区 医学 Q1 CELL BIOLOGY
Nitin Kumar Pokhrel, Amanda R. Panfil, Haniya Habib, Shamreethaa Seeniraj, Ancy Joseph, Daniel Rauch, Linda Cox, Robert Sprung, Petra Erdmann Gilmore, Qiang Zhang, Robert Reid Townsend, Lianbo Yu, Ayse Selen Yilmaz, Rajeev Aurora, William Park, Lee Ratner, Katherine N. Weilbaecher, Deborah J. Veis
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引用次数: 0

Abstract

Adult T cell leukaemia (ATL), caused by infection with human T- lymphotropic virus type 1 (HTLV-1), is often complicated by hypercalcemia and osteolytic lesions. Therefore, we studied the communication between patient-derived ATL cells (ATL-PDX) and HTLV-1 immortalized CD4+ T cell lines (HTLV/T) with osteoclasts and their effects on bone mass in mice. Intratibial inoculation of some HTLV/T leads to a profound local decrease in bone mass similar to marrow-replacing ATL-PDX, despite the fact that few HTLV/T cells persisted in the bone. To study the direct effect of HTLV/T and ATL-PDX on osteoclasts, supernatants were added to murine and human osteoclast precursors. ATL-PDX supernatants from hypercalcemic patients promoted the formation of mature osteoclasts, while those from HTLV/T were variably stimulatory, but had largely consistent effects between human and murine cultures. Interestingly, this osteoclastic activity did not correlate with expression of osteoclastogenic cytokine receptor activator of nuclear factor kappa-B ligand (RANKL), suggesting an alternative mechanism. HTLV/T and ATL-PDX produce small extracellular vesicles (sEV), known to facilitate HTLV-1 infection. We hypothesized that these sEV also mediate bone loss by targeting osteoclasts. We isolated sEV from both HTLV/T and ATL-PDX, and found they carried most of the activity found in supernatants. In contrast, sEV from uninfected activated T cells had little effect. Analysis of sEV (both active and inactive) by mass spectrometry and electron microscopy confirmed absence of RANKL and intact virus. Viral proteins Tax and Env were only present in sEV from the active, osteoclast-stimulatory group, along with increased representation of proteins involved in osteoclastogenesis and bone resorption. sEV from osteoclast-active HTLV/T injected over mouse calvaria in the presence of low-dose RANKL caused more osteolysis than osteoclast-inactive sEV or RANKL alone. Thus, HTLV-1 infection of T cells can cause release of sEV with strong osteolytic potential, providing a mechanism beyond RANKL production that modifies the bone microenvironment, even in the absence of overt leukaemia.

Abstract Image

受 HTLV-1 感染的 T 细胞通过细胞外小泡导致骨质流失。
由人类 T 淋巴细胞病毒 1 型(HTLV-1)感染引起的成人 T 细胞白血病(ATL)通常会并发高钙血症和溶骨性病变。因此,我们研究了患者衍生的 ATL 细胞(ATL-PDX)和 HTLV-1 永生化 CD4+ T 细胞系(HTLV/T)与破骨细胞之间的交流及其对小鼠骨量的影响。胫骨内接种一些 HTLV/T,会导致局部骨量显著下降,与骨髓置换 ATL-PDX 相似,尽管事实上很少有 HTLV/T 细胞持续存在于骨骼中。为了研究 HTLV/T 和 ATL-PDX 对破骨细胞的直接影响,将上清液添加到小鼠和人类破骨细胞前体中。来自高钙血症患者的 ATL-PDX 上清液促进了成熟破骨细胞的形成,而来自 HTLV/T 的上清液则有不同程度的刺激作用,但对人类和小鼠培养物的影响基本一致。有趣的是,这种破骨细胞活性与破骨细胞生成细胞因子受体激活剂核因子卡巴-B配体(RANKL)的表达无关,这表明存在另一种机制。HTLV/T和ATL-PDX会产生小细胞外囊泡(sEV),已知这些囊泡会促进HTLV-1感染。我们假设这些 sEV 也会通过靶向破骨细胞来介导骨质流失。我们从 HTLV/T 和 ATL-PDX 中分离出了 sEV,发现它们具有上清液中发现的大部分活性。相比之下,未感染的活化 T 细胞中的 sEV 作用很小。通过质谱法和电子显微镜分析 sEV(包括活性和非活性),证实其中不含 RANKL 和完整的病毒。破骨细胞活性 HTLV/T 的 sEV 在低剂量 RANKL 存在的情况下注射到小鼠小腿上,比破骨细胞活性 sEV 或单独注射 RANKL 引起的溶骨更多。因此,HTLV-1 感染 T 细胞可导致释放具有强烈溶骨潜能的 sEV,提供了一种 RANKL 之外的机制,即使在没有明显白血病的情况下也能改变骨微环境。
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来源期刊
Journal of Extracellular Vesicles
Journal of Extracellular Vesicles Biochemistry, Genetics and Molecular Biology-Cell Biology
CiteScore
27.30
自引率
4.40%
发文量
115
审稿时长
12 weeks
期刊介绍: The Journal of Extracellular Vesicles is an open access research publication that focuses on extracellular vesicles, including microvesicles, exosomes, ectosomes, and apoptotic bodies. It serves as the official journal of the International Society for Extracellular Vesicles and aims to facilitate the exchange of data, ideas, and information pertaining to the chemistry, biology, and applications of extracellular vesicles. The journal covers various aspects such as the cellular and molecular mechanisms of extracellular vesicles biogenesis, technological advancements in their isolation, quantification, and characterization, the role and function of extracellular vesicles in biology, stem cell-derived extracellular vesicles and their biology, as well as the application of extracellular vesicles for pharmacological, immunological, or genetic therapies. The Journal of Extracellular Vesicles is widely recognized and indexed by numerous services, including Biological Abstracts, BIOSIS Previews, Chemical Abstracts Service (CAS), Current Contents/Life Sciences, Directory of Open Access Journals (DOAJ), Journal Citation Reports/Science Edition, Google Scholar, ProQuest Natural Science Collection, ProQuest SciTech Collection, SciTech Premium Collection, PubMed Central/PubMed, Science Citation Index Expanded, ScienceOpen, and Scopus.
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