Dudakov Jarrod A, Mertelsmann Anna M, O'Connor Margaret H, Jenq Robert R, Velardi Enrico, Young Lauren F, Smith Odette M, Boyd Richard L, van den Brink Marcel R M, Hanash Alan M
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY.
Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Blood. 2017 Aug 17;130(7):933-942. doi: 10.1182/blood-2017-01-762658. Epub 2017 Jun 12.
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.
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相关并发症。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尚不清楚。在此，我们在实验小鼠模型中证明，GVHD导致胸腺再生所需的胸腺内3型固有淋巴细胞（ILC3s）耗竭。与无GVHD的移植受者相比，胸腺ILC3s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（TECs）保护并损害胸腺生成的恢复。相反，消除供体T细胞中的IL-21受体信号并抑制胸腺ILC的清除以IL-22依赖的方式改善了胸腺生成。我们发现，通过恢复IL-22信号传导可改善与ILC丢失相关的GVHD中的胸腺生成障碍。尽管同种异体反应未受抑制，但移植后给予外源性IL-22可导致胸腺生成恢复增加以及新的胸腺来源外周T细胞的发育。我们的研究强调了固有免疫功能在胸腺再生和移植后适应性免疫恢复中的作用。操纵ILC-IL-22-TEC轴可能有助于增强临床造血移植和其他T细胞缺陷情况下的免疫重建。
