Recipient expression of C-type lectin receptor Mincle promotes rapid T cell homeostatic recovery following antibody mediated lymphoablation

Abstract

Abstract Antibody-mediated lymphocyte depletion is widely used in transplantation. We recently showed 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 FcRγ-coupled C-type lectin receptor that binds ligands released by pathogens or damaged cells 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. The NanoString and RT-PCR analyses of B cells showed that mATG depletion resulted in B cell up-regulation of Mincle and Card-9 gene expression. Flow cytometry confirmed cell surface Mincle expression in B cells from mATG-treated recipients but not from naïve mice. Treatment with 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 recipients treated with mATG had severely impaired T cell recovery and significantly prolonged allograft survival compared to WT recipients. We propose that B cells activation via CD40 results in up-regulation of cell surface Mincle. Endogenous ligands released from necrotic graft cells bind to Mincle thus inducing B cells to secrete proinflammatory cytokines and facilitate CD8+ T cell proliferation. These data identify Mincle as a novel therapeutic target to improve the efficacy of lymphoablation in allograft recipients.