LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L
LAG-3, TGF-β, and cell-intrinsic PD-1 inhibitory pathways contribute to CD8 but not CD4 T-cell tolerance induced by allogeneic BMT with anti-CD40L
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DOI：
10.1182/blood-2010-11-318675
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发表时间：
2011-05-19
期刊：
影响因子：
20.3
通讯作者：
Sykes, Megan
中科院分区：
文献类型：
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作者：
Lucas, Carrie L.;Workman, Creg J.;Sykes, Megan
同种异体骨髓移植时给予单剂量抗cd40l单抗可耐受外周同种异体反应性T细胞，并允许在小鼠中建立混合造血嵌合。一旦移植，混合嵌合体通过中心缺失机制对供体Ags具有全身耐受性，并将无限期地接受任何供体器官。我们之前发现，在这个模型中，PD-1/PD-L1通路是CD8 t细胞耐受所必需的。然而，必须表达PD-1的细胞群和其他抑制分子的作用尚不清楚。在这里，我们报告了LAG-3是长期外周CD8耐受所必需的，而不是CD4 t细胞耐受所必需的，并且这种要求是CD8细胞外源性的。相比之下，过继性转移研究显示，CD8 T细胞对CTLA4/B7.1/B7.2和PD-1的内在需求诱导CD8 T细胞耐受。我们还观察到，供体细胞独立需要PD-L1和PD-L2来实现t细胞耐受性。最后，我们发现在这个体内系统中，tgf - β信号需要进入T细胞以实现外周CD8而不是CD4 T细胞耐受。(Blood.2011; 117 (20): 5532 - 5540)
Administration of a single dose of anti-CD40L mAb at the time of allogeneic BM transplantation tolerizes peripheral alloreactive T cells and permits establishment of mixed hematopoietic chimerism in mice. Once engrafted, mixed chimeras are systemically tolerant to donor Ags through a central deletion mechanism and will accept any donor organ indefinitely. We previously found that the PD-1/PD-L1 pathway is required for CD8 T-cell tolerance in this model. However, the cell population that must express PD-1 and the role of other inhibitory molecules were unknown. Here, we report that LAG-3 is required for long-term peripheral CD8 but not CD4 T-cell tolerance and that this requirement is CD8 cell-extrinsic. In contrast, adoptive transfer studies revealed a CD8 T cell-intrinsic requirement for CTLA4/B7.1/B7.2 and for PD-1 for CD8 T-cell tolerance induction. We also observed that both PD-L1 and PD-L2 are independently required on donor cells to achieve T-cell tolerance. Finally, we uncovered a requirement for TGF-beta signaling into T cells to achieve peripheral CD8 but not CD4 T-cell tolerance in this in vivo system. (Blood.2011; 117(20):5532-5540)