Concomitant loss of regulatory T and B cells is a distinguishing immune feature of antibody-mediated rejection in kidney transplantation.
Concomitant loss of regulatory T and B cells is a distinguishing immune feature of antibody-mediated rejection in kidney transplantation.
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调节性T细胞和B细胞的同时缺失是肾移植中抗体介导的排斥反应的显著免疫特征。
DOI：
10.1016/j.kint.2021.12.027
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发表时间：
2022-05
影响因子：
19.6
通讯作者：
Metes, Diana
中科院分区：
文献类型：
--
作者：
Louis, Kevin;Fadakar, Paul;Macedo, Camila;Yamada, Masaki;Lucas, Michelle;Gu, Xinyan;Zeevi, Adriana;Randhawa, Parmjeet;Lefaucheur, Carmen;Metes, Diana
尽管在理解导致抗体介导的排斥反应（ABMR）的供体特异性抗体生成的细胞效应机制方面已经取得了相当大的进展，但仍缺乏对此类免疫反应的细胞调节因子的鉴定。为了澄清这一点，我们使用高维流式细胞术同时分析和跟踪血液中调节性淋巴细胞的两个主要亚群：96 名肾移植受者的队列中的调节性 T 细胞 (TREG) 和过渡性 B 细胞。此外，我们建立了共培养测定法，以解决它们各自在体外抑制抗体反应的能力。研究发现，TREG 和移行 B 细胞是滤泡辅助 T 细胞介导的 B 细胞分化为浆母细胞和抗体生成的有效抑制因子。在移植后未产生供体特异性抗体的患者中，TREG 和移行 B 细胞均得到持久扩增。然而，表现出供者特异性抗体并进展为 ABMR 的患者则表现出 TREG 和移行 B 细胞数量显着且持续的减少。引人注目的是，ABMR 患者的 TREG 和移行 B 细胞区室中表达转录因子 T-bet 的特定细胞簇被选择性地耗尽。重要的是，这些 T-bet+CXCR5+TREG 和 T-bet+CD21− 移行 B 细胞簇的协调丢失与炎症供体特异性抗体反应的增加、更广泛的微血管炎症和更高的肾同种异体移植丢失率相关。因此，我们的研究发现接受 ABMR 的患者调节性 T 和 B 细胞反应存在协调和持续的缺陷，这可能导致他们体液免疫调节的丧失，并需要及时的治疗干预来补充和维持这些患者的 TREG 和移行 B 细胞。
Although considerable advances have been made in understanding the cellular effector mechanisms responsible for donor-specific antibody generation leading to antibody-mediated rejection (ABMR), the identification of cellular regulators of such immune responses is lacking. To clarify this, we used high dimensional flow cytometry to concomitantly profile and track the two major subsets of regulatory lymphocytes in blood: T regulatory (TREG) and transitional B cells in a cohort of 96 kidney transplant recipients. Additionally, we established co-culture assays to address their respective capacity to suppress antibody responses in vitro. TREG and transitional B cells were found to be potent suppressors of T follicular helper-mediated B cell differentiation into plasmablast and antibody generation. TREG and transitional B cells were both durably expanded in patients who did not develop donor-specific antibody post-transplant. However, patients who manifested donor-specific antibody and progressed to ABMR displayed a marked and persistent numerical reduction in TREG and transitional B cells. Strikingly, specific cell clusters expressing the transcription factor T-bet were selectively depleted in both TREG and transitional B cell compartments in patients with ABMR. Importantly, the coordinated loss of these T-bet+CXCR5+TREG and T-bet+CD21− transitional B cell clusters was correlated with increased and inflammatory donor specific antibody responses, more extensive microvascular inflammation and a higher rate of kidney allograft loss. Thus, our study identified coordinated and persistent defects in regulatory T and B cell responses in patients undergoing ABMR, which may contribute to their loss of humoral immune regulation, and warrant timely therapeutic interventions to replenish and sustain TREG and transitional B cells in these patients.
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影响因子：
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