T-bet+CD27+CD21- B cells poised for plasma cell differentiation during antibody-mediated rejection of kidney transplants
T-bet+CD27+CD21- B cells poised for plasma cell differentiation during antibody-mediated rejection of kidney transplants
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DOI：
10.1172/jci.insight.148881
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发表时间：
2021-06-22
期刊：
影响因子：
8
通讯作者：
Metes, Diana
中科院分区：
文献类型：
--
作者：
Louis, Kevin;Bailly, Elodie;Metes, Diana
供体特异性抗体（DSA）引起的同种异体免疫反应可导致器官移植中抗体介导的排斥反应（ABMR）。然而，同种异体反应性B细胞反应的细胞状态和控制它们的分子组分仍然不清楚。通过对96例肾移植受者的B细胞进行高维分析，我们发现在发生DSA并进展为ABMR的患者中，CD 27（+）CD 21（-）激活的记忆（AM）B细胞表达转录因子T-bet。值得注意的是，AM细胞在DSA（+）ABMR（-）患者中较少见，在DSA（-）患者中处于基线水平。在经历ABMR的患者中AM细胞的RNA-Seq分析揭示了这些细胞准备用于浆细胞分化并且表达反映克隆扩增的限制性IGHV序列。除了T-bet，AM细胞表现出干扰素调节因子4和Blimp 1的表达升高，并在与自体T滤泡辅助细胞共培养后，以IL-21依赖的方式分化为DSA产生的浆细胞。AM细胞的出现频率与ABMR表现的时间和严重程度相关。重要的是，T-bet（+）AM细胞与其限制性IGHV序列一起沿着在肾移植物中被检测到。这项研究描绘了一个关键的作用，AM细胞在促进体液反应和ABMR在器官移植，并强调他们作为重要的治疗靶点。
Alloimmune responses driven by donor-specific antibodies (DSAs) can lead to antibody-mediated rejection (ABMR) in organ transplantation. Yet, the cellular states underlying alloreactive B cell responses and the molecular components controlling them remain unclear. Using high-dimensional profiling of B cells in a cohort of 96 kidney transplant recipients, we identified expanded numbers of CD27(+)CD21(-) activated memory (AM) B cells that expressed the transcription factor T-bet in patients who developed DSAs and progressed to ABMR. Notably, AM cells were less frequent in DSA(+)ABMR(-) patients and at baseline levels in DSA(-)patients. RNA-Seq analysis of AM cells in patients undergoing ABMR revealed these cells to be poised for plasma cell differentiation and to express restricted IGHV sequences reflective of clonal expansion. In addition to T-bet, AM cells manifested elevated expression of interferon regulatory factor 4 and Blimp1, and upon coculture with autologous T follicular helper cells, differentiated into DSA-producing plasma cells in an IL-21-dependent manner. The frequency of AM cells was correlated with the timing and severity of ABMR manifestations. Importantly, T-bet(+) AM cells were detected within kidney allografts along with their restricted IGHV sequences. This study delineates a pivotal role for AM cells in promoting humoral responses and ABMR in organ transplantation and highlights them as important therapeutic targets.