Massive Activation-Induced Cell Death of Alloreactive T Cells With Apoptosis of Bystander Postthymic T Cells Prevents Immune Reconstitution in Mice With Graft-Versus-Host Disease
Massive Activation-Induced Cell Death of Alloreactive T Cells With Apoptosis of Bystander Postthymic T Cells Prevents Immune Reconstitution in Mice With Graft-Versus-Host Disease
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DOI：
10.1182/blood.v94.2.390
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发表时间：
1999-07
期刊：
影响因子：
20.3
通讯作者：
S. Brochu;B. Rioux-Massé;J. Roy;D. Roy;C. Perreault
中科院分区：
文献类型：
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作者：
S. Brochu;B. Rioux-Massé;J. Roy;D. Roy;C. Perreault
造血干细胞移植后，移植的成熟胸腺后T细胞的持久性和扩增允许供体免疫记忆的转移和多样化T细胞库的产生。这种胸腺非依赖性过程在人类中特别重要，因为大多数移植受者都表现出严重的胸腺萎缩，移植物抗宿主病（GVHD）损害了这一过程。本研究的目的是破译GVHD如何影响移植胸腺后T细胞的命运。有两个主要发现。首先，我们发现，在一个活跃的增殖阶段后，同种异体反应性抗宿主T细胞经历了大规模活化诱导的细胞死亡（AICD）。对于CD4+和CD8+ T细胞，发现Fas途径在这种AICD中起主要作用：同种异体反应性T细胞上调Fas和FasL，并且在lpr（Fas缺陷）供体的情况下，抗宿主T细胞的AICD大大降低。第二，而非宿主反应性供体T细胞既不上调Fas，也没有遭受单独移植时，细胞凋亡，他们表现出增加膜Fas表达和细胞凋亡时，共注射与宿主反应性T细胞。我们的结论是，GVHD相关的AICD的抗宿主T细胞加上旁观者裂解移植的非宿主反应性T细胞废除供体来源的胸腺后T淋巴细胞的免疫重建。此外，我们推测，大量的淋巴细胞凋亡，在急性期观察到的GVHD可能是负责在慢性期的GVHD的自身免疫的发生。
After hematopoietic stem cell transplantation, the persistence and expansion of grafted mature postthymic T cells allow both transfer of donor immunologic memory and generation of a diverse T repertoire. This thymic-independent process, which is particularly important in humans, because most transplant recipients present severe thymus atrophy, is impaired by graft-versus-host disease (GVHD). The goal of this study was to decipher how GVHD influences the fate of grafted postthymic T cells. Two major findings emerged. First, we found that, after a brisk proliferation phase, alloreactive antihost T cells underwent a massive activation-induced cell death (AICD). For both CD4+ and CD8+ T cells, the Fas pathway was found to play a major role in this AICD: alloreactive T cells upregulated Fas and FasL, and AICD of antihost T cells was much decreased in the case of lpr (Fas-deficient) donors. Second, whereas non–host-reactive donor T cells neither upregulated Fas nor suffered apoptosis when transplanted alone, they showed increased membrane Fas expression and apoptosis when coinjected with host-reactive T cells. We conclude that GVHD-associated AICD of antihost T cells coupled with bystander lysis of grafted non–host-reactive T cells abrogate immune reconstitution by donor-derived postthymic T lymphocytes. Furthermore, we speculate that massive lymphoid apoptosis observed in the acute phase of GVHD might be responsible for the occurrence of autoimmunity in the chronic phase of GVHD.