*Purpose: Alloimmunity triggered by donor-specific antibodies (DSAs) and ensuing development of antibody-mediated rejection (ABMR) are detrimental to organ transplants. Yet, the cellular states underlying B cell alloreactive responses and the molecular components controlling them remain unclear.

*Methods: We used high dimensional B cell profiling in blood and tissue in a cohort of 96 kidney transplant recipients.

*Results: We identified expanded clusters of CD27+CD21- activated memory (AM) and CD27-CD21- tissue-like memory (TLM) B cells that expressed the transcription factor T-bet in blood of patients who developed DSA and progressed to ABMR (DSA+ABMR+, N=20). AM and TLM cells were diminished in DSA+ABMR- (N=28) patients and at baseline levels in DSA- (N=48) patients. Unlike TLM cells that displayed cell exhaustion features, AM cells manifested elevated expression of IRF4 and Blimp1, and upon co-culture with autologous circulating T follicular helper (cTFH) cells differentiated into DSA-producing plasma cells in an IL-21 dependent manner. Comparative RNA-seq analysis of AM with TLM and resting memory B cells in patients undergoing ABMR revealed a distinctive transcriptional state and selective expression of IGHV sequences reflective of clonal expansion. The T-bet expressing AM cells preferentially accumulated in patients with severe ABMR and were correlated with increased frequency of activated cTFH cells, skewed generation of DSAs towards IgG3 isotypes and increased vascular lesions in kidney allografts. AM cells and their distinct molecular signatures were also detected within kidney allografts of patients undergoing ABMR.

*Conclusions: This study suggests a pivotal role for T-bet expressing AM B cells in directing humoral alloimmune responses against organ transplants leading to ABMR and may represent an important therapeutic target.

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