Induction of TGF-β1, Not Regulatory T Cells, Impairs Antiviral Immunity in the Lung following Bone Marrow Transplant
Induction of TGF-β1, Not Regulatory T Cells, Impairs Antiviral Immunity in the Lung following Bone Marrow Transplant
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DOI：
10.4049/jimmunol.0901871
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发表时间：
2010-05-01
影响因子：
4.4
通讯作者：
Moore, Bethany B.
中科院分区：
文献类型：
--
作者：
Coomes, Stephanie M.;Wilke, Carol A.;Moore, Bethany B.
接受造血干细胞移植或骨髓移植（BMT）治疗各种恶性肿瘤或自身免疫性疾病的患者，移植后感染并发症的风险增加，尤其是在肺部。我们已经在小鼠和鼠γ疱疹病毒，γ HV-68中使用BMT来研究BMT后适应性免疫应答的功效。移植后五周，小鼠在肺和外周都完全重建了造血谱系。然而，当用病毒攻击时，BMT小鼠从肺中清除裂解病毒的能力降低。BMT小鼠的病毒控制缺陷与白细胞募集受损或APC功能缺陷无关。相反，BMT小鼠的特征是CD 4细胞增殖缺陷，效应CD 4 T细胞从Th 1向Th 17表型倾斜，以及感染时的免疫抑制性肺环境，包括TGF-β 1和PGE的过表达（2）和调节性T细胞数量增加。吲哚美辛治疗阻断PG合成和抗CD 25耗竭调节性T细胞都不能改善BMT后的抗病毒宿主防御。用在允许的CD 4启动子下表达显性阴性TGF-β RII的转基因骨髓移植小鼠，产生了效应CD 4和CD 8细胞对TGF-β 1无反应的小鼠。具有TGF-β 1非应答效应T细胞的小鼠在BMT后恢复了抗病毒免疫力并改善了Th 1应答。因此，我们的研究结果表明，骨髓移植后清髓性条件反射后TGF-β 1的过度表达导致效应T细胞对病毒感染的应答受损。免疫学杂志，2010，184：5130-5140。
Patients receiving hematopoietic stem cell transplantation or bone marrow transplantation (BMT) as therapy for various malignancies or autoimmune diseases have an increased risk for infectious complications posttransplant, especially in the lung. We have used BMT in mice and murine gammaherpesvirus, gamma HV-68, to study the efficacy of adaptive immune responses post-BMT. Five weeks posttransplant, mice have fully reconstituted their hematopoietic lineages in both the lung and periphery. When challenged with virus, however, BMT mice have a reduced ability to clear lytic virus from the lung. Defective viral control in BMT mice is not related to impaired leukocyte recruitment or defective APC function. Rather, BMT mice are characterized by defective CD4 cell proliferation, skewing of effector CD4 T cells from a Th1 to a Th17 phenotype, and an immunosuppressive lung environment at the time of infection that includes overexpression of TGF-beta 1 and PGE(2) and increased numbers of regulatory T cells. Neither indomethacin treatment to block PG synthesis nor anti-CD25 depletion of regulatory T cells improved antiviral host defense post-BMT. Transplanting mice with transgenic bone marrow expressing a dominant-negative TGF-beta RII under the permissive CD4 promoter created mice in which effector CD4 and CD8 cells were unresponsive to TGF-beta 1. Mice with TGF-beta 1 nonresponsive effector T cells had restored antiviral immunity and improved Th1 responses post-BMT. Thus, our results indicate that overexpression of TGF-beta 1 following myeloablative conditioning post-BMT results in impaired effector T cell responses to viral infection. The Journal of Immunology, 2010, 184: 5130-5140.