Session Time: 3:15pm-4:45pm
Presentation Time: 4:15pm-4:27pm
*Purpose: The role of alloreactive memory B (mB) cells in the pathogenesis of antibody-mediated rejection (ABMR) is increasingly recognized. Yet, a comprehensive characterization of mB cell heterogeneity during ongoing donor-specific antibody (DSA) responses is lacking.
*Methods: Using 22-color flow cytometry and in vitro assays, we investigated the immune phenotype and function of blood subsets of mB cells in patients who did not develop DSA (DSA-, N=48) and in patients who developed DSA (DSA+, N=48) post kidney transplantation and in healthy controls (HC, N=17).
*Results: We have identified three distinct subsets of blood CD20+CD38lo mB cells: resting memory (RM, CD27+CD21+Tbet–), activated memory (AM, CD27+CD21–Tbetint) and tissue-like memory (TLM, CD27–CD21–Tbethi) B cells. AM and TLM were significantly expanded in blood of DSA+ patients (P=0.001 for both), while RM mB cells were the predominant subset in DSA- patients and in HC. AM, unlike RM or TLM mB cells, strongly correlated with the plasmablast response (r=0.57, P=0.003), and circulating DSA levels (r=0.73, P<0.001). In DSA+ patients who developed ABMR (N=20), AM but not RM or TLM mB cells were selectively expanded and peaked at the time of biopsy-proven rejection. Phenotypically, AM mB cells upregulated multiple activation markers (Ki67, CD86 and CD95 ; P<0.001 for all) and readily expressed plasma cell markers (Blimp and IRF4 ; P<0.001 for both). In contrast, TLM mB cells expressed increased inhibitory receptors (FcγRIIb, CD72 and FcRL5 ; P<0.001 for all) and strongly downregulated CD40 (P=0.002), suggesting their hypo-responsiveness to T-cell help. Consistently, when co-cultured with T follicular helper cells (TFH), TLM poorly differentiated into plasmablast and did not produce IgG, while AM mB cells highly differentiated into plasmablast and produced DSA in vitro.
*Conclusions: We identified functional heterogeneity in CD21– mB cells during ABMR. AM were enriched for alloantigen-specific cells and prone to plasmablast differentiation upon TFH-cell help, while TLM mB cells were TFH-cell independent and prone to regulation/exhaustion. Timely detection and selective targeting of deleterious AM mB-cell response represent valuable strategies to prevent ABMR.
To cite this abstract in AMA style:Louis K, Bailly E, Macedo C, Marrari M, Yamada M, Randhawa P, Zeevi A, Lefaucheur C, Metes D. Activated CD27+CD21– Subset Dominate the Memory B Cell Response During Antibody-Mediated Rejection of Kidney Allografts [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/activated-cd27cd21-subset-dominate-the-memory-b-cell-response-during-antibody-mediated-rejection-of-kidney-allografts/. Accessed March 1, 2021.
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