Marginal zone B cells are responsible for the production of alloantibodies following platelet transfusion in mice

Alloimmunization against platelets remains a potentially serious adverse transfusion event. Alloantibodies produced by the recipient, mainly directed against HLA I donor antigens, can compromise the therapeutic efficacy of subsequent transfusions and may lead to refractoriness. Since the mechanism of anti-HLA alloantibody formation is poorly understood, the aim of this work was to identify the cells involved in the platelet immune response by focusing on the spleen, the main organ described to orchestrate this alloimmune response. In the spleen, transfused allogeneic platelets were located in the marginal zone and interacted with marginal zone B (MZB) cells, a specialized B cell population implicated in the capture and follicular delivery of blood-borne antigens. To study the involvement of MZB cells in alloantibody production, we used a murine model reproducing the MHC incompatibility between a donor (H2b) and a recipient (H2d) which occurs during platelet transfusion. Following weekly H2b platelet transfusions, recipient H2d mice produced anti-H2b IgG inducing a refractory state upon subsequent transfusions. Specific immunodepletion of MZB cells, or their displacement from the marginal zone to the B cell follicles by treatment with an S1P1 antagonist before each transfusion, prevented significant alloantibody formation. Under these conditions, transfused platelets were still circulating after 24 h, whereas they were rapidly removed from the circulation of alloimmunized mice. The identification of MZB cells as key players in the platelet alloimmune response opens up new perspectives to minimize platelet alloimmunization and avoid the associated refractory state in frequently transfused patients.