Macrophage‐inducible C‐type lectin activates B cells to promote T cell reconstitution in heart allograft recipients

Diminishing homeostatic proliferation of memory T cells is essential for improving the efficacy of lymphoablation in transplant recipients. Our previous studies in a mouse heart transplantation model established that B lymphocytes secreting proinflammatory cytokines are critical for T cell recovery after lymphoablation. The goal of the current study was to identify mediators of B cell activation following lymphoablation in allograft recipients. Transcriptome analysis revealed that macrophage‐inducible C‐type lectin (Mincle, Clec4e) expression is up‐regulated in B cells from heart allograft recipients treated with murine anti‐thymocyte globulin (mATG). Recipient Mincle deficiency diminishes B cell production of pro‐inflammatory cytokines and impairs T lymphocyte reconstitution. Mixed bone marrow chimeras lacking Mincle only in B lymphocytes have similar defects in T cell recovery. Conversely, treatment with a synthetic Mincle ligand enhances T cell reconstitution after lymphoablation in non‐transplanted mice. Treatment with agonistic CD40 mAb facilitates T cell reconstitution in CD4 T cell‐depleted, but not in Mincle‐deficient, recipients indicating that CD40 signaling induces T cell proliferation via a Mincle‐dependent pathway. These findings are the first to identify an important function of B cell Mincle as a sensor of damage‐associated molecular patterns released by the graft and demonstrate its role in clinically relevant settings of organ transplantation.