Targeting the CD19/CD21 complex on B cells in the mixed lymphocyte reaction

B cells exert antigen presenting functions at the crossroad between immune activation and tolerance induction, a fate notably governed by the B Cell Receptor (BCR) response regulator CD19/CD21 complex. This duality in B cells raises a particular interest in the case of acute graft-versus-host disease (GvHD), a common complication post allogeneic haematopoietic stem cell transplantation (HSCT). In this context, B cells may act either through the disruption of their capacity to present antigensin an attempt to passively hamper GvHD onset, or, conversely, by harnessing their tolerogenic potential to actively protect host tissues from cytotoxic killing by donor T cells. Hence deciphering a way to fine tune B cell functions to fit these purposes is critical. Here, we proposed that the maintenance of B cells in a resting state with the concourse of the anti-CD22 antibody epratuzumab, inducing reduction in surface CD19/CD21 complex, would mitigate their responsiveness to allopeptides and thus, prevent the acquisition of potent antigen presenting functions. Furthermore, the combination with C3d adjunction would direct antigensto CD21-mediated uptake for class II MHC presentation, taking advantage of the incapacity to derive any costimulatory activities as part of this process. The subset of B cells hereby generated would therefore have constituted a large repertoire of antigens towards which a tolerogenic state would be established. The plausibility of this strategy was investigated in a newly designed mixed lymphocyte reaction (MLR) model in which we attempted to integrate critical component of the cytokine network at the backbone of aGvHD pathophysiology, IL-15, stemming as a result of the post-HSCT lymphopenia and initial tissue damage induced by the pre-conditioning regiment. We found a dichotomy in the effect mediated by C3d. It decreased by 1.46-fold granzyme b production when used alone, but failed to sustain such effects when used in conjunction with epratuzumab. The reduction in CD19/CD21 expression induced by epratuzumab could potentially account for this outcome as CD2llow B cells are reported to be anergic. C3d usually has a role in breaking tolerance, however an opposite effect was observed here. The targeting of C3d-coated antigens to CD21 independent of BCR engagement appears to be taking place. This study provides an insight on the potential of fine-tuning the CD19/CD21 complex and sets the foundation for future research to better characterise the events taking place. This is crucial for the better optimisation of putative therapeutic strategies targeting the CD19/CD21 complex in the settings of aGvHD.