T follicular Helper Cells in Transplantation: Specialized Helpers Turned Rogue.
T follicular Helper Cells in Transplantation: Specialized Helpers Turned Rogue.
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DOI：
10.1097/tp.0000000000001218
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发表时间：
2016-08
期刊：
影响因子：
6.2
通讯作者：
Metes DM
中科院分区：
文献类型：
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作者：
Metes DM
戴安娜·M·梅特斯，MD1器官移植代表了终末期器官衰竭相关疾病的治疗选择。尽管医学上取得了重大进展，器官共享和分配网络组织良好，可获得新的和更有效的免疫抑制方案，但器官移植后的长期结果仍然不理想，到10年时，同种异体移植物的平均存活率仅为50%。1同种异体移植排斥反应是同种异体移植物失败的重要原因，包括针对同种异体移植物的多层细胞和/或体液免疫损伤。供体特异性抗人类白细胞抗原抗体(DSA)在移植受者中的存在最近已成为同种异体移植预后不良的一个重要的生物标志物。2例如，大约30%的高度致敏的肾移植受者在移植后出现显著的DSA血清滴度，这与抗体介导的排斥反应(AMR)的风险增加相关，随后，慢性排斥和同种异体移植失败的发生率更高。DSA是针对人类白细胞抗原分子的同型转换、补体结合的免疫球蛋白抗体，依赖于CD4+T细胞帮助B细胞的产生。在CD4+T细胞中，最近发现的滤泡辅助T细胞(TFH)被认为是专门控制细菌或病毒感染和疫苗接种后抗原特异性B细胞生理性抗体反应的大小和质量的细胞亚群。3、4此外，在自身免疫中，TFH在致病抗体反应中起着关键作用。3、4T滤泡辅助细胞参与次级淋巴器官生发中心(GC)的形成，为B淋巴细胞分化为记忆性B细胞、长寿浆细胞以及产生滤泡外浆母细胞提供关键帮助，从而对产生高亲和力的免疫球蛋白G反应起关键作用。T滤泡辅助细胞的特征是：(I)表达B细胞淋巴瘤6，这是导致TFH发生的转录抑制因子；(Ii)表达CXC趋化因子受体5，一种趋化因子受体，驱动TFH细胞向毛囊中的CXC趋化因子配体13+B细胞；(Iii)共刺激/共抑制分子，可诱导T细胞共刺激分子CD40L和程序性细胞死亡受体1的共同表达；(Iv)产生IL-21。3、4此外，TFH细胞的活性似乎受到调节性T细胞的紧密调控，这可能进一步控制抗体反应的大小和输出。5在TFH细胞研究领域的另一个重要进展是最近在外周血中发现了人循环CXC趋化因子受体5+CD4+TFH细胞，这是监测免疫后或慢性抗体介导性疾病患者TFH细胞活性(即抗体反应)的理想替代细胞。7循环中的TFH约占外周血记忆中CD4+T细胞的20%，在功能上是不同的，由Th1-TFH、Th2-TFH和Th17-TFH亚群组成，这些亚群是在启动时响应不同的环境提示而产生的。4有趣的是，尽管在知识上取得了所有这些进展，但TFH细胞对同种免疫的直接贡献，特别是对导致AMR的DSA发展的直接贡献，在器官移植领域尚未完全了解，因此许多方面仍有待阐明。在本期《移植》杂志中，Walters和Vinuesa8对TFH细胞生物学进行了全面的概述，讨论了TFH细胞移植研究的现有文献，并强调了该领域的进展和局限性。他们进一步讨论了治疗性…
Diana M. Metes, MD1 Organ transplantation represents the treatment of choice for end-stage organ failure–associated diseases. Despite significant advances in medicine, well-organized networks of organ sharing and distribution, and availability of novel and more potent immunosuppressive regimens, longterm outcomes after organ transplantation remain suboptimal, with an average of only 50% allograft survival by 10 years. 1 Allograft rejection is 1 important etiology of allograft failure and consists of multilayered cellular and/or humoral immunologic injuries against the allograft. The presence of donor-specific anti-HLA antibodies (DSA) in transplant recipients has recently emerged as a significant biomarker of poor allograft outcomes. 2 For example, approximately 30% of highly sensitized kidney transplant recipients present with significant serum titers of DSA posttransplantation that correlate with increased risk of antibody-mediated rejections (AMR) and, later on, with higher incidence of chronic rejection and allograft failure. DSA are isotype switched, complement-binding IgG antibodies directed against HLA molecules, and depend on CD4+ T cell help to B cells for their generation. Among CD4+ T cells, the recently discovered follicular helper T cells (TFH) are recognized to be the subset of cells specialized in the cognate control of the magnitude and quality of antigen-specific B-cell physiologic antibody responses after bacterial or viral infections, and vaccination. 3, 4 In addition, TFH proved pivotal to pathogenic antibody responses in autoimmunity. 3, 4 T follicular helper cells are demonstrated to participate to the germinal center (GC) formation in the secondary lymphatic organs, where they provide critical help to B lymphocytes to differentiate into memory B cells, longlived plasma cells, as well as to generate extrafollicular plasmablasts, and thus critical to the production of high-affinity IgG responses. T follicular helper cells are characterized by the (i) expression of B cell lymphoma 6, the transcriptional repressor factor responsible for TFH development;(ii) the expression of CXC chemokine receptor 5, a chemokine receptor that drives TFH cells toward CXC chemokine ligand 13+ B cells in follicles;(iii) the coexpression of costimulatory/coinhibitory molecules inducible T cell costimulator, CD40L, and programmed cell death receptor 1;(iv) production of IL-21. 3, 4 Moreover, the TFH cell activity seems to be tightly modulated by regulatory T cells, which may further control the size and output of the antibody responses. 5 Another important advance in the field of TFH cell research was the recent identification and characterization of human circulating CXC chemokine receptor 5+CD4+ TFH cells in peripheral blood, ideal surrogate cells to monitor TFH cell activity (ie, Ab responses) postvaccination or in patients with chronic antibody-mediated diseases. 6, 7 Circulating TFH represent approximately 20% of peripheral blood memory CD4+ T cells, are functionally heterogeneous, and are comprised of Th1-TFH, Th2-TFH, and Th17-TFH subsets generated in response to distinct environmental cues at priming. 4 Interestingly, despite all these advances in knowledge, the direct contribution of TFH cells to alloimmunity, and specifically to DSA development leading to AMR, has not been totally understood in the field of organ transplantation, and therefore many aspects remain to be elucidated. In this issue of Transplantation, Walters and Vinuesa8 provide a comprehensive overview on the TFH cell biology, discuss the available literature on TFH cell research in transplantation, and highlight the progress and limitations in the field. They further discuss therapeutic …