Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor β1-positive regulatory T cells and begins in early infection
Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor β1-positive regulatory T cells and begins in early infection
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DOI：
10.1086/510852
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发表时间：
2007-02-15
影响因子：
6.4
通讯作者：
Haase, Ashley T.
中科院分区：
文献类型：
--
作者：
Estes, Jacob D.;Wietgrefe, Stephen;Haase, Ashley T.
在人类免疫缺陷病毒（HIV）感染中，T细胞区内的胶原沉积和纤维化破坏淋巴组织结构，导致CD 4（+）T细胞耗竭并限制免疫重建。我们使用相关的动物和体外模型来研究该过程的动力学和可能的潜在机制。在猴免疫缺陷病毒（SIV）感染的恒河猴的淋巴组织中，我们观察到免疫激活、转化生长因子（TGF）β 1阳性调节性T（T-reg）细胞和I型胶原沉积在接种后7天平行增加，这与早期免疫激活激发对抗与TGF β 1表达和胶原沉积相关的Treg细胞反应的假设一致。为了支持这一假说和纤维化在病毒发病机制中的可能作用，我们显示：（1）TGF β 1（+）Treg细胞和胶原沉积水平的空间共定位和时间一致性;（2）TGF β 1（+）诱导的T-reg细胞刺激原代淋巴组织成纤维细胞产生I型胶原;（3）与免疫激活、TGF β 1（+）T-reg细胞和胶原沉积水平较低的白眉猴的非致病性SIV感染相比，猕猴的致病性SIV感染中免疫激活、TGF β 1（+）T-reg细胞和胶原沉积水平较高。因此，我们得出结论，TGF β 1（+）Treg细胞对早期SIV/HIV感染中免疫激活的反应是一把双刃剑：TGF β 1（+）T-reg细胞通常通过限制免疫病理学和自身反应性免疫反应而产生积极作用，但它们也通过抑制抗病毒免疫反应而产生负面影响，正如我们在这里所展示的，通过诱导淋巴组织中的胶原沉积而对CD 4（+）T细胞稳态产生有害影响。
In human immunodeficiency virus (HIV) infection, collagen deposition and fibrosis within the T cell zone disrupt the lymphatic tissue architecture, contributing to depletion of CD4(+) T cells and limiting immune reconstitution. We used relevant animal and in vitro models to investigate the kinetics and possible underlying mechanism(s) of this process. In the lymphatic tissue of simian immunodeficiency virus (SIV)-infected rhesus macaques, we observed parallel increases in immune activation, transforming growth factor (TGF) beta 1-positive regulatory T (T-reg) cells, and collagen type I deposition by 7 days after inoculation, consistent with the hypothesis that early immune activation elicits a countering Treg cell response associated with TGF beta 1 expression and collagen deposition. In support of this hypothesis and the possible role of fibrosis in viral pathogenesis, we show (1) spatial colocalization and temporal concordance in levels of TGF beta 1(+) Treg cells and collagen deposition; (2) TGF beta 1(+) inducible T-reg cell stimulation of primary lymphatic tissue fibroblasts to produce collagen type I in vitro; and (3) high levels of immune activation, TGF beta 1(+) T-reg cells, and collagen deposition in pathogenic SIV infection of macaques, in contrast to apathogenic SIV infection in sooty mangabeys in which levels of immune activation, TGF beta 1(+) T-reg cells, and collagen deposition were low. We thus conclude that the response of TGF beta 1(+) Treg cells to immune activation in early SIV/HIV infection is a double-edged sword: TGF beta 1(+) T-reg cells normally have a positive effect by limiting immunopathological and autoreactive immune responses, but they also have a negative effect by dampening the antiviral immune response and, as we show here, causing deleterious effects on CD4(+) T cell homeostasis by inducing collagen deposition in lymphatic tissues.