Abstract
Pretransplant donor lymphocyte infusion (DLI) has been shown to enhance donor-specific allograft survival in rodents, primates and humans. However, the cell subset that is critical for the DLI effect and the mechanisms involved remain elusive. In this study, we monitored donor cell subsets after DLI in a murine MHC class I Ld-mismatched skin transplantation model. We found that donor B cells, but not DCs, are the major surviving donor APCs in recipients following DLI. Infusing donor B, but not non-B, cells resulted in significantly enhanced donor-specific skin allograft survival. Furthermore, mice that had received donor B cells showed higher expression of Ly6A and CD62L on antigen-specific TCRαβ+CD3+CD4−CD8−NK1.1− double negative (DN) regulatory T cells (Tregs). B cells presented alloantigen to DN Tregs and primed their proliferation in an antigen-specific fashion. Importantly, DN Tregs, activated by donor B cells, showed increased cytotoxicity toward anti-donor CD8+ T cells. These data demonstrate that donor B cells can enhance skin allograft survival, at least partially, by increasing recipient DN Treg-mediated killing of anti-donor CD8+ T cells. These findings provide novel insights into the mechanisms underlying DLI-induced transplant tolerance and suggest that DN Tregs have great potential as an antigen-specific immune therapy to enhance allograft survival.
Highlights
Pretransplant donor specific transfusion or donor lymphocyte infusion (DLI) has been used either alone or in combination with other treatments to prolong graft survival in various animal models and in clinical settings [1,2,3,4,5,6]
As Ly6A expression on double negative (DN) Tregs was significantly increased in mice that received donor B cell infusion (Fig. 4A–B), we addressed the question of whether infusion of donor B cells would increase the ability of DN Tregs to kill syngeneic anti-donor CD8+ T cells in vivo
These findings further suggest that DN Tregs that were activated by donor B cells may possess enhanced cytotoxicity toward anti-donor CD8+ T cells
Summary
Pretransplant donor specific transfusion or donor lymphocyte infusion (DLI) has been used either alone or in combination with other treatments to prolong graft survival in various animal models and in clinical settings [1,2,3,4,5,6]. The mechanism by which DLI induces donor-specific transplantation tolerance is poorly defined. DLI-induced graft survival has been shown to be directly correlated with the infused lymphocytes in the recipients [7]. As B cells have been shown to play critical roles in both graft rejection and tolerance, further understanding the role of B cells in transplantation will facilitate the development of novel B cell directed strategies as well as modify previous B cell therapies to achieve donor-specific transplant tolerance [13,14]
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