Ayasoufi K, Fan R, Valujskikh A
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH.
Am J Transplant. 2017 Aug;17(8):2008-2019. doi: 10.1111/ajt.14309. Epub 2017 May 17.
Lymphoablation is routinely used in transplantation, and its success is defined by the balance of pathogenic versus protective T cells within reconstituted repertoire. While homeostatic proliferation and thymopoiesis may both cause T cell recovery during lymphopenia, the relative contributions of these mechanisms remain unclear. The goal of this study was to investigate the role of the thymus during T cell reconstitution in adult allograft recipients subjected to lymphoablative induction therapy. Compared with euthymic mice, thymectomized heart allograft recipients demonstrated severely impaired CD4 and CD8 T cell recovery and prolonged heart allograft survival after lymphoablation with murine anti-thymocyte globulin (mATG). The injection with agonistic anti-CD40 mAb or thymus transplantation only partially restored T cell reconstitution in mATG-treated thymectomized mice. After mATG depletion, residual CD4 T cells migrated into the thymus and enhanced thymopoiesis. Conversely, depletion of CD4 T cells before lymphoablation inhibited thymopoiesis at the stage of CD4 CD8 CD44 CD25 immature thymocytes. This is the first demonstration that the thymus and peripheral CD4 T cells cooperate to ensure optimal T cell reconstitution after lymphoablation. Targeting thymopoiesis through manipulating functions of depletion-resistant helper T cells may thus improve therapeutic benefits and minimize the risks of lymphoablation in clinical settings.
淋巴细胞清除术在移植中经常使用，其成功与否取决于重建库中致病性T细胞与保护性T细胞之间的平衡。虽然稳态增殖和胸腺生成在淋巴细胞减少期间都可能导致T细胞恢复，但这些机制的相对贡献仍不清楚。本研究的目的是调查胸腺在接受淋巴细胞清除诱导治疗的成年同种异体移植受者T细胞重建过程中的作用。与正常胸腺小鼠相比，胸腺切除的心脏同种异体移植受者在用鼠抗胸腺细胞球蛋白（mATG）进行淋巴细胞清除后，CD4和CD8 T细胞恢复严重受损，心脏同种异体移植存活时间延长。注射激动性抗CD40单克隆抗体或进行胸腺移植仅部分恢复了mATG处理的胸腺切除小鼠的T细胞重建。mATG清除后，残留的CD4 T细胞迁移到胸腺并增强胸腺生成。相反，在淋巴细胞清除前耗尽CD4 T细胞会在CD4 CD8 CD44 CD25未成熟胸腺细胞阶段抑制胸腺生成。这首次证明胸腺和外周CD4 T细胞相互协作以确保淋巴细胞清除后最佳的T细胞重建。因此，通过操纵抗耗竭辅助性T细胞的功能来靶向胸腺生成可能会改善治疗效果，并在临床环境中最小化淋巴细胞清除的风险。
