BCR signaling is required for posttransplant lymphoproliferative disease in immunodeficient mice receiving human B...

Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of a lack of suitable models for mechanistic characterization. Here, we show that ex vivo-differentiated B cells isolated from a subset of healthy donors can elicit pathologies similar to PTLD when transferred into immunodeficient mice. The primary driver of PTLD-like pathologies were IgM-producing plasmablasts with Epstein-Barr virus (EBV) genomes that expressed genes commonly associated with EBV latency. We show that a small subset of EBV⁺ peripheral blood-derived B cells expressing self-reactive, nonmutated B cell receptors (BCRs) expand rapidly in culture in the absence of BCR stimulation. Furthermore, we found that in vitro and in vivo expansion of EBV⁺ plasmablasts required BCR signaling. Last, treatment of immunodeficient mice with the BCR pathway inhibitor, ibrutinib, delays onset of PTLD-like pathologies in vivo. These data have implications for the diagnosis and care of transplant recipients who are at risk of developing PTLD.