Session Time: 3:15pm-4:45pm
Presentation Time: 3:51pm-4:03pm
*Purpose: Antibody-mediated lymphocyte depletion is widely used in transplantation. We recently established that T cell recovery in mouse heart allograft recipients treated with anti-thymocyte globulin (mATG) depends on B cells activated via CD40 and is mediated by B cell-derived IL-1β and IL-6. Mincle (Clec-4e) is a C-type lectin receptor that binds exogenous and endogenous ligands released by damaged cells, couples with FcRγ and signals through the Card-9 pathway. While Mincle functions are well characterized in myeloid cells, its significance in B cells remains to be determined. Our goal was to investigate the role of Mincle in initiating B cell cytokine production in lymphopenic heart allograft recipients.
*Methods: B6 (H-2b) recipients of BALB/c (H-2d) heart allografts were treated with mATG at (d. 0, 4). The gene expression in isolated spleen B cells was analyzed by NanoString and validated by real-time RT-PCR. Mincle expression in recipient spleen cell subsets was evaluated by flow cytometry. To prevent CD40-mediated B cell activation, recipients were treated with anti-CD154 mAb (d. -1) prior to heart transplantation and mATG treatment. In addition, Mincle KO mice were used as heart allograft recipients and treated with mATG.
*Results: Compared to untreated heart allograft recipients, mATG depletion resulted in B cell up-regulation of Mincle and Card-9 gene expression. Flow cytometry analyses confirmed cell surface Mincle expression in B cells from mATG-treated allograft recipients but not from naïve mice. Administration of anti-CD154 mAb in addition to mATG decreased the B cell expression of Mincle, IL-1β, IL-6 and TNF-α. Moreover, B cell IL-1β and TNF-α expression were reduced in mATG treated Mincle KO allograft recipients compared to WT controls. Most importantly, Mincle KO heart allograft recipients treated with mATG had severely impaired T cell reconstitution and significantly prolonged heart allograft survival compared to control WT recipients (MST of 25 vs 11 d, n=4).
*Conclusions: Our findings support the following model: B cells activation via CD40 results in up-regulation of cell surface Mincle. Endogenous ligands released from necrotic heart allograft cells bind to Mincle (and potentially other PRRs) thus inducing B lymphocytes to secrete proinflamatory cytokines and facilitate CD8+ T cell proliferation. These data identify Mincle as a novel therapeutic target to alleviate inflammation and improve the efficacy of lymphoablation in allograft recipients.
To cite this abstract in AMA style:Hasgur S, Fan R, Valujskikh A. Recipient Expression of C-Type Lectin Receptor Mincle Promotes Rapid T Cell Homeostatic Recovery Following Antibody Mediated Lymphoablation [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/recipient-expression-of-c-type-lectin-receptor-mincle-promotes-rapid-t-cell-homeostatic-recovery-following-antibody-mediated-lymphoablation/. Accessed April 15, 2021.
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