Abstract
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.
Highlights
Humoral alloimmunity mediated by anti–human leukocyte antigen donor-specific antibodies (DSAs) significantly impedes prolonged survival of allografts after organ transplantation [1,2,3]
T-bet+ activated memory (AM) cells were detected within kidney allografts of Antibody-mediated rejection (ABMR) patients along with their characteristic amplified IGHV sequences, supporting their pathogenic role in allograft rejection
We observed a significant increase in the frequencies of total B cells in DSA+ABMR+ patients as compared with DSA– patients and Healthy control (HC) that was due to higher frequencies of memory B cell (MBC) and plasmablasts
Summary
Humoral alloimmunity mediated by anti–human leukocyte antigen (anti-HLA) donor-specific antibodies (DSAs) significantly impedes prolonged survival of allografts after organ transplantation [1,2,3]. T-bet–expressing B cells, including age-associated B cells, display multiple common phenotypic and functional attributes conserved in humans, such as the overexpression of the integrin CD11c and the activation markers CD86 and CD95, as well as the downregulation of the classical B cell markers CD23, CD24, and CD38. These cells can function as potent effectors or display features of exhaustion [12, 13]. Flu or yellow fever vaccines have been shown to strongly induce CD27+CD21– T-bet–expressing
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