B lymphocytes contribute to indirect pathway T cell sensitization via acquisition of extracellular vesicles

Abstract

B cells have been implicated in transplant rejection via antibody‐mediated mechanisms and more recently by presenting donor antigens to T cells. We have shown in patients with chronic antibody‐mediated rejection that B cells control the indirect T cell alloresponses. To understand more about the role of B cells as antigen‐presenting cells for CD4+ T cell with indirect allospecificity, B cells were depleted in C57BL/6 mice, using an anti‐CD20 antibody, prior to receiving MHC class I–mismatched (Kd) skin. The absence of B cells at the time of transplantation prolonged skin graft survival. To study the mechanisms behind this observation, T cells with indirect allospecificity were transferred in mice receiving a Kd skin transplant. T cell proliferation was markedly inhibited in the absence of recipient B cells, suggesting that B cells contribute to indirect pathway sensitization. Furthermore, we have shown that a possible way in which B cells present alloantigens is via acquisition of MHC‐peptide complexes. Finally, we demonstrate that the addition of B cell depletion to the transfer of regulatory T cells (Tregs) with indirect alloresponse further prolonged skin graft survival. This study supports an important role for B cells in indirect T cell priming and further emphasizes the advantage of combination therapies in prolonging transplant survival.

Advances in Liver Transplantation: where are we in the pursuit of transplantation tolerance?

“…Moreover, we have recently provided further evidence in support of previously published work, reporting the additional advantage of combination therapy to increase the efficacy of allospecific Tregs [60,61]. Using an MHC class I mismatched skin transplantation mouse model, we demonstrated the role of B cells in antigen presentation and activation of T cells with indirect allospecificity.…”

Extracellular Vesicles From Kidney Allografts Express miR-218-5p and Alter Th17/Treg Ratios

“…Allorecognition occurs through two distinct pathways: the "direct" pathway whereby recipient T cells recognize intact donor HLA on the surface of donor APCs and the "indirect" pathway where recipient T cells recognize processed donor HLA-peptides by self-HLA molecules (32)(33)(34). Recently, the concept of "semi direct" antigen presentation has emerged in the context of EV; allograftderived EV can interact with recipient APCs, which then present donor HLA molecules on their surface, a phenomenon known as HLA "cross-dressing" (14,(35)(36)(37)(38)(39).…”

Extracellular Vesicles in Transplantation

“…This suggests that host APCs can acquire donor MHC molecules present on EVs secreted by donor cells and thereby initiate immune responses and further determine the fate of the allograft in a semi-direct pathway (24). In another study, Becker et al, described the role of EVs in allograft recognition in an indirect pathway (49). The semi-direct pathway have been linked with the cross dressing of donor class I MHC onto host APC that favors the "three cell model" of alloreactive CD8+ T cell activation (50).…”