Zhang Yi, Joe Gerard, Hexner Elizabeth, Zhu Jiang, Emerson Stephen G
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
J Immunol. 2005 Mar 1;174(5):3051-8. doi: 10.4049/jimmunol.174.5.3051.
Graft-vs-host disease (GVHD) is caused by a donor T cell anti-host reaction that evolves over several weeks to months, suggesting a requirement for persistent alloreactive T cells. Using the C3H.SW anti-C57BL/6 (B6) mouse model of human GVHD directed against minor histocompatibility Ags, we found that donor CD8(+) T cells secreting high levels of IFN-gamma in GVHD B6 mice receiving C3H.SW naive CD8(+) T cells peaked by day 14, declined by day 28 after transplantation, and persisted thereafter, corresponding to the kinetics of a memory T cell response. Donor CD8(+) T cells recovered on day 42 after allogeneic bone marrow transplantation expressed the phenotype of CD44(high)CD122(high)CD25(low), were able to homeostatically survive in response to IL-2, IL-7, and IL-15 and rapidly proliferated upon restimulation with host dendritic cells. Both allogeneic effector memory (CD44(high)CD62L(low)) and central memory (CD44(high)CD62L(high)) CD8(+) T cells were identified in B6 mice with ongoing GVHD, with effector memory CD8(+) T cells as the dominant (>80%) population. Administration of these allogeneic memory CD8(+) T cells into secondary B6 recipients caused virulent GVHD. A similar allogeneic memory CD4(+) T cell population with the ability to mediate persistent GVHD was also identified in BALB/b mice receiving minor histocompatibility Ag-mismatched B6 T cell-replete bone marrow transplantation. These results indicate that allogeneic memory T cells are generated in vivo during GVH reactions and are able to cause GVHD, resulting in persistent host tissue injury. Thus, in vivo blockade of both alloreactive effector and memory T cell-mediated host tissue injury may prove to be valuable for GVHD prevention and treatment.
移植物抗宿主病（GVHD）由供体T细胞抗宿主反应引起，该反应会在数周至数月内逐渐发展，这表明需要持续存在的同种异体反应性T细胞。使用针对次要组织相容性抗原的人GVHD的C3H.SW抗C57BL/6（B6）小鼠模型，我们发现，在接受C3H.SW天然CD8⁺T细胞的GVHD B6小鼠中，分泌高水平干扰素-γ的供体CD8⁺T细胞在第14天达到峰值，移植后第28天下降，并在之后持续存在，这与记忆T细胞反应的动力学一致。同种异体骨髓移植后第42天恢复的供体CD8⁺T细胞表达CD44⁽高⁾CD122⁽高⁾CD25⁽低⁾的表型，能够在白细胞介素-2、白细胞介素-7和白细胞介素-15的作用下稳态存活，并在用宿主树突状细胞再次刺激后迅速增殖。在患有持续性GVHD的B6小鼠中鉴定出同种异体效应记忆（CD44⁽高⁾CD62L⁽低⁾）和中枢记忆（CD44⁽高⁾CD62L⁽高⁾）CD8⁺T细胞，其中效应记忆CD8⁺T细胞为主要（>80%）群体。将这些同种异体记忆CD8⁺T细胞给予二级B6受体可导致严重的GVHD。在接受次要组织相容性抗原不匹配的B6 T细胞充足骨髓移植的BALB/b小鼠中，也鉴定出了具有介导持续性GVHD能力的类似同种异体记忆CD4⁺T细胞群体。这些结果表明，同种异体记忆T细胞在GVH反应期间在体内产生，并且能够引起GVHD，导致宿主组织持续损伤。因此，在体内阻断同种异体反应性效应和记忆T细胞介导的宿主组织损伤可能对GVHD预防和治疗具有重要价值。
