Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease
Loss of thymic innate lymphoid cells leads to impaired thymopoiesis in experimental graft-versus-host disease
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DOI：
10.1182/blood-2017-01-762658
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发表时间：
2017-08-17
期刊：
影响因子：
20.3
通讯作者：
Hanash, Alan M.
中科院分区：
文献类型：
--
作者：
Dudakov, Jarrod A.;Mertelsmann, Anna M.;Hanash, Alan M.
移植物抗宿主病（GVHD）和移植后免疫缺陷是异基因造血移植常见的并发症。同种异体反应性供体T细胞可损伤胸腺上皮，从而限制新的T细胞发育。尽管胸腺在损伤后具有显著的再生能力，但在GVHD中内源性胸腺再生受损。导致这种再生失败的机制在很大程度上是未知的。在这里，我们证明在实验小鼠模型中，GVHD的结果在胸腺内组3先天淋巴细胞（ILC 3）胸腺再生所必需的耗竭。与无GVHD的移植受者相比，胸腺ILC 3的缺失导致胸腺内白细胞介素-22（IL-22）缺乏，从而抑制IL-22介导的胸腺上皮细胞（TEC）保护作用并损害胸腺生成的恢复。相反，废除供体T细胞中的IL-21受体信号传导并抑制胸腺ILC的消除以IL-22依赖的方式改善胸腺生成。我们发现，在GVHD中与ILC丢失相关的胸腺生成障碍可以通过恢复IL-22信号转导来改善。尽管不受抑制的同种异体反应性，外源性IL-22移植后管理导致增加恢复的胸腺生成和新的胸腺衍生的外周T细胞的发展。我们的研究强调了先天免疫功能在胸腺再生和移植后适应性免疫恢复中的作用。ILC-IL-22-TEC轴的操纵可用于在临床造血移植和T细胞缺乏的其他设置后增强免疫重建。
Graft-versus-host disease (GVHD) and posttransplant immunodeficiency are frequently related complications of allogeneic hematopoietic transplantation. Alloreactive donor T cells can damage thymic epithelium, thus limiting new T-cell development. Although the thymus has a remarkable capacity to regenerate after injury, endogenous thymic regeneration is impaired in GVHD. The mechanisms leading to this regenerative failure are largely unknown. Here we demonstrate in experimental mouse models that GVHD results in depletion of intrathymic group 3 innate lymphoid cells (ILC3s) necessary for thymic regeneration. Loss of thymic ILC3s resulted in deficiency of intrathymic interleukin-22 (IL-22) compared with transplant recipients without GVHD, thereby inhibiting IL-22-mediated protection of thymic epithelial cells (TECs) and impairing recovery of thymopoiesis. Conversely, abrogating IL-21 receptor signaling in donor T cells and inhibiting the elimination of thymic ILCs improved thymopoiesis in an IL-22-dependent fashion. We found that the thymopoietic impairment in GVHD associated with loss of ILCs could be improved by restoration of IL-22 signaling. Despite uninhibited alloreactivity, exogenous IL-22 administration posttransplant resulted in increased recovery of thymopoiesis and development of new thymus-derived peripheral T cells. Our study highlights the role of innate immune function in thymic regeneration and restoration of adaptive immunity posttransplant. Manipulation of the ILC-IL-22-TEC axis may be useful for augmenting immune reconstitution after clinical hematopoietic transplantation and other settings of T-cell deficiency.