*Purpose: Although considerable advances have been made in understanding the cellular effector mechanisms responsible for donor-specific antibody (DSA) generation leading to antibody-mediated rejection (ABMR), the identification of cellular regulators of such immune responses is lacking.

*Methods: In a cohort of 96 kidney transplant recipients, we used high dimensional flow cytometry to concomitantly profile and track the two major subsets of regulatory lymphocytes in blood: T regulatory (T_REG) and transitional B (TrB) cells. Additionally, we established co-culture assays to address their respective capacity to suppress antibody responses in vitro.

*Results: T_REG and TrB were potent suppressors of T follicular helper-mediated B cell differentiation into plasmablast and antibody generation. While T_REG and TrB were both durably expanded in patients who did not develop DSA post-transplant, patients who manifested DSA and progressed to ABMR displayed a marked and persistent numerical reduction in T_REG and TrB cells. Strikingly, specific cell clusters expressing the transcription factor T-bet were selectively depleted in both T_REG and TrB compartments in patients with ABMR. Importantly, the coordinated loss of these T-bet⁺CXCR5⁺ T_REG and T-bet⁺CD21^– TrB cell clusters was correlated with increased and inflammatory DSA responses, more extensive microvascular inflammation and higher rate of kidney allograft loss.

*Conclusions: Our study identified coordinated and persistent defects in the regulatory T and B cell responses in patients undergoing ABMR, which may contribute to their loss of humoral immune regulation, and thus, warranting timely therapeutic interventions to replenish and sustain T_REG and TrB cells in these patients.

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