Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy
Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy
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DOI：
10.1016/j.bbmt.2006.05.014
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发表时间：
2006-09-01
影响因子：
4.3
通讯作者：
Fowler, Daniel H.
中科院分区：
文献类型：
--
作者：
Jung, Unsu;Foley, Jason E.;Fowler, Daniel H.
雷帕霉素预防小鼠移植物抗宿主病（GVHD）与向Th2-和tc2型细胞因子转移有关。最近，我们发现在体外供体Th2细胞生成过程中使用雷帕霉素可以增强过继转移的Th2细胞预防小鼠GVHD的能力。在这项研究中，我们使用了一种不使用抗原提呈细胞的方法，基于CD3、CD28共刺激的t细胞扩增，我们评估了(1)相对于Th1/Tc1细胞，雷帕霉素是否优先促进Th2/Tc2细胞的产生，(2)雷帕霉素产生的t细胞亚群是否在同种异体骨髓移植（BMT）后诱导细胞因子偏斜，以及(3)这种体内细胞因子偏斜对雷帕霉素治疗后敏感。与我们的假设相反，雷帕霉素并没有优先促进Th2/Tc2细胞的极性，因为雷帕霉素产生的Th1/Tc1细胞分泌I型细胞因子（白细胞介素[IL]-2和干扰素- γ），而不分泌II型细胞因子（IL-4、IL-5、IL-10或IL-13）和介导的fasl细胞溶解。雷帕霉素影响t细胞分化，因为雷帕霉素产生的Th1、Th2、Tc1和Tc2亚群中的每一个都增加了中央记忆t细胞标记物l-选择素（CD62L）的表达。雷帕霉素产生的Th1/Tc1和Th2/Tc2细胞不是无能细胞，而是在体外共刺激后扩增增加，在体内经BAIT后扩增增加，在BMT后分别保持完全向I型或II型细胞因子倾斜的能力；此外，与对照Th1/Tc1细胞相比，雷帕霉素产生的Th1/Tc1细胞介导的致死性GVHD增加。接受雷帕霉素生成的Th1/Tc1细胞BMT后雷帕霉素治疗可显著降低Th1/Tc1细胞数量，显著降低I型细胞因子，降低致死性GVHD；与之形成鲜明对比的是，在接受雷帕霉素生成的Th2/Tc2细胞的受体中，雷帕霉素治疗名义上影响了体内Th2/Tc2细胞的数量，并没有消除bmt后II型细胞因子的偏斜。综上所述，体外和体内使用雷帕霉素可用于调节Th1/Tc1和Th2/Tc2细胞亚群的bmt后平衡。(C) 2006年美国血液和骨髓移植学会。
Rapamycin prevention of murine graft-versus-host disease (GVHD) is associated with a shift toward Th2- and Tc2-type cytokines. Recently, we found that use of rapamycin during ex vivo donor Th2 cell generation enhances the ability of adoptively transferred Th2 cells to prevent murine GVHD. In this study, using a method, without antigen-presenting cells, of T-cell expansion based on CD3,CD28 costimulation, we evaluated whether (1) rapamycin preferentially promotes the generation of Th2/Tc2 cells relative to Th1/Tc1 cells, (2) rapamycin-generated T-cell subsets induce cytokine skewing after allogeneic bone marrow transplantation (BMT), and (3) such in vivo cytokine skewing is sensitive to post-BAIT rapamycin therapy. Contrary to our hypothesis, rapamycin did not preferentially promote Th2/Tc2 cell polarity, because rapamycin-generated Th1/Tc1 cells secreted type I cytokines (interleukin [IL]-2 and interferon-gamma) did not secrete type II cytokines (IL-4, IL-5, IL-10, or IL-13) and mediated fasL-based cytolysis. Rapamycin influenced T-cell differentiation, because each of the Th1, Th2, Tc1, and Tc2 subsets generated in rapamycin had increased expression of the central-memory T-cell marker, L-selectin (CD62L). Rapamycin-generated Th1/Tc1 and Th2/Tc2 cells were not anergic but instead had increased expansion after costimulation in vitro, increased expansion in vivo after BAIT, and maintained full capacity to skew toward type I or II cytokines after BMT, respectively; further, rapamycin-generated Th1/Tc1 cells mediated increased lethal GVHD relative to control Th1/Tc1 cells. Rapamycin therapy after BMT in recipients of rapamycin-generated Th1/Tc1 cells greatly reduced Th1/Tc1 cell number, greatly reduced type I cytokines, and reduced lethal GVHD; in marked contrast, rapamycin therapy in recipients of rapamycin-generated Th2/Tc2 cells nominally influenced the number of Th2/Tc2 cells in vivo and did not abrogate post-BMT type II cytokine skewing. In conclusion, ex vivo and in vivo usage of rapamycin may be used to modulate the post-BMT balance of Th1/Tc1 and Th2/Tc2 cell subsets. (C) 2006 American Society for Blood and Marrow Transplantation.