TGFβ-dependent expression of PD-1 and PD-L1 controls CD8(+) T cell anergy in transplant tolerance.
TGFβ-dependent expression of PD-1 and PD-L1 controls CD8(+) T cell anergy in transplant tolerance.
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作者：
Baas M;Besançon A;Goncalves T;Valette F;Yagita H;Sawitzki B;Volk HD;Waeckel-Enée E;Rocha B;Chatenoud L;You S
CD8+T细胞无能是外周免疫耐受的重要机制，但对免疫治疗的反应研究较少。在这里，使用同种异体胰岛移植模型和CD3抗体治疗，我们通过单细胞基因图谱显示，移植物内共表达颗粒酶B和穿孔素的CD8+淋巴细胞通过Fas/FasL途径选择性地被耗尽。这一步骤导致剩余的CD8+T细胞长期无能，其标志是缺乏细胞毒/炎症基因的表达，转录组分析也证实了这一点。这种持续的无反应需要同种异体抗原的存在。此外，组织内CD8+淋巴细胞产生转化生长因子β，并表达抑制受体PD-1和PD-L1。阻断转化生长因子β可下调PD-1和PD-L1的表达，促进移植物排斥反应。中和T细胞中的PD-1、PD-L1或转化生长因子CD3RII信号也可消除β抗体诱导的耐受。这些研究揭示了CD8+T细胞无能的新机制，并揭示了转化生长因子β和PD-1/PD-L1通路之间的细胞内在调控联系。DOI：http://dx.doi.org/10.7554/eLife.08133.001免疫系统总是警惕感染的迹象或生病的细胞。当这些迹象被识别出来时，一种名为CD8+T细胞的白细胞亚群迅速行动起来，数量增加，然后采取行动消除潜在的威胁。虽然这种反应对于抵抗感染和癌症等其他疾病至关重要，但它可能会对器官移植患者产生适得其反的效果。事实上，CD8+T细胞可以靶向并攻击移植器官的细胞，导致身体排斥该器官。避免移植排斥的一种方法是关闭已经学会识别移植细胞的CD8+T细胞。事实上，2012年和2013年的研究表明，用结合T细胞的抗体治疗移植动物可以保护移植器官免受攻击。这种治疗必须在CD8+T细胞识别并开始靶向移植器官才能有效。但目前还不清楚这种抗体治疗是如何保护移植的。现在，巴斯，贝桑松等人。-包括一些参与早期研究的研究人员-表明治疗中使用的抗体选择性地靶向并消除攻击CD8+T细胞。这样只会留下不活跃的CD8+T细胞，不会对移植造成损害。为了做到这一点，巴斯、贝桑松等人。将小鼠的胰腺细胞移植到其他患有糖尿病样疾病的小鼠体内。接下来，实验比较了接受抗体治疗和未接受治疗的小鼠移植组织中CD8+T细胞的基因表达。在抗体治疗后，许多有毒分子的基因表达被阻止，使CD8+T细胞处于不活跃状态。此外，经过处理的CD8+T细胞更多地表达了一种特定类型的受体(称为PD-1和PD-L1)，该受体充当免疫系统的抑制性检查点。那么，Baas，Besançon等人。用消除T细胞的抗体和阻断这些抑制性受体的抗体来治疗移植的小鼠，看看会发生什么。移植的器官很快遭到攻击和排斥。这表明，在最初的抗体治疗中，抑制性受体在帮助关闭攻击CD8+T细胞并允许移植器官长期存活方面发挥了关键作用。在抗体处理的小鼠中阻断另一种名为转化生长因子β的蛋白质也会导致器官排斥。这些发现有助于解释这些抗体是如何保护移植器官的，并可能帮助科学家在未来试图开发新的抗移植排斥药物。DOI：http://dx.doi.org/10.7554/eLife.08133.002
CD8+ T cell anergy is a critical mechanism of peripheral tolerance, poorly investigated in response to immunotherapy. Here, using a pancreatic islet allograft model and CD3 antibody therapy, we showed, by single cell gene profiling, that intragraft CD8+ lymphocytes coexpressing granzyme B and perforin were selectively depleted through the Fas/FasL pathway. This step led to long-standing anergy of the remaining CD8+ T cells marked by the absence of cytotoxic/inflammatory gene expression also confirmed by transcriptome analysis. This sustained unresponsiveness required the presence of the alloantigens. Furthermore, tissue-resident CD8+ lymphocytes produced TGFβ and expressed the inhibitory receptors PD-1 and PD-L1. Blockade of TGFβ downregulated PD-1 and PD-L1 expression and precipitated graft rejection. Neutralizing PD-1, PD-L1 or TGFβRII signaling in T cells also abrogated CD3 antibody-induced tolerance. These studies unravel novel mechanisms underlying CD8+ T cell anergy and reveal a cell intrinsic regulatory link between the TGFβ and the PD-1/PD-L1 pathways. DOI: http://dx.doi.org/10.7554/eLife.08133.001 The immune system is always on guard for signs of infection or cells that have become diseased. When these signs are identified, a subset of white blood cells called CD8+ T cells leap into action, multiply in number and then act to eliminate the potential threat. While this response is essential to fighting off infections and other diseases like cancer, it can backfire in people with an organ transplant. Indeed, the CD8+ T cells can target and attack the cells of the transplanted organ causing the body to reject the organ. One way to avoid transplant rejection would be to turn off CD8+ T cells that have learned to recognize cells from the transplant. In fact, studies in 2012 and 2013 showed that treating transplanted animals with an antibody that binds T cells protects a transplanted organ from attack. This treatment had to be given after the CD8+ T cells had recognized and began targeting the transplanted organ to be effective. But it was not clear exactly how this antibody treatment protected the transplant. Now, Baas, Besançon et al. – including some of the same researchers involved in the earlier studies – show that the antibodies used in the treatment selectively target and eliminate the attacking CD8+ T cells. This leaves behind only inactive CD8+ T cells that don’t harm the transplant. To do this, Baas, Besançon et al. transplanted pancreatic cells from mice into other mice with a diabetes-like disorder. Next, the experiments compared gene expression in CD8+ T cells found within the transplanted tissue in mice that were treated with the antibody and those that were not treated. The expression of many genes for toxic molecules was stopped after treatment with the antibody leaving the CD8+ T cells in an inactive state. In addition, the treated CD8+ T cells expressed more of a certain type of receptor (called PD-1 and PD-L1) that acts as inhibitory checkpoint for the immune system. So, Baas, Besançon et al. treated transplanted mice with both the T cell-eliminating antibody and antibodies that block these inhibitory receptors to see what would happen. The transplanted organs were quickly attacked and rejected. This shows that the inhibitory receptors play a crucial role in helping to shut down attacking CD8+ T cells in the initial antibody treatment and allowed long-term survival of the transplanted organs. Blocking another protein called TGFβ in antibody-treated mice also caused organ rejection. The findings help explain how these antibodies protect transplanted organs and may help scientists trying to develop new anti-transplant rejection drugs in the future. DOI: http://dx.doi.org/10.7554/eLife.08133.002