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• W3048579723 abstract "In the context of solid organ transplantation, Becker et al. (page 1415) show that semidirect presentation of donor MHC antigens acquired from donor extracellular vesicles by recipient B cells can initiate the alloimmune response, thus challenging the canonical passenger leukocyte theory. In the context of solid organ transplantation, Becker et al. (page 1415) show that semidirect presentation of donor MHC antigens acquired from donor extracellular vesicles by recipient B cells can initiate the alloimmune response, thus challenging the canonical passenger leukocyte theory. In the field of solid organ transplantation, de novo donor-specific antibodies of IgG isotype (DSA) are negatively correlated with graft function and survival. Over the last decades, B cells have unveiled biological functions shared with other cell types such as immune regulation and antigen presentation that are relevant in solid organ transplantation. Antigen presentation (direct, indirect, and semi-direct) are key mechanisms in allo-immunity since they can occur in the early phase of solid organ transplantation, triggering cellular and humoral adaptive immunity, which lasts during the transplant life and may lead to rejection mainly due to major histocompatibility complex (MHC) mismatch between donor and recipient. Brand new data from G. Lombardi’s team shed new light on the role of recipient B cells in indirect presentation of donor MHC peptides to recipient T cells, inducing their activation in the early phase of skin transplantation in a murine model depleted of CD8+ T cells and dendritic cells (DCs) by administration of a monoclonal antibody (α-CD8).1Becker PD Ratnasothy K Sen M et al.B lymphocytes contribute to indirect pathway T cell sensitization via acquisition of extracellular vesicles.Am J Transplant. 2020; (https://doi.org/10.1111/ajt.16088): 1-12Google Scholar They observed that skin transplant rejection was significantly delayed when B cells were depleted in secondary lymphoid organs (SLO) and in medulla 7 days before skin transplantation. In this model, the allospecific priming of CD4+ T cells was delayed, independently of regulatory IL10+ B cells. These results were in line with those from a cohort of kidney-transplanted patients with chronic antibody-mediated rejection where circulating recipient B cells efficiently amplified recipient T cell responses against the renal transplant with indirect allospecificities.2Shiu KY McLaughlin L Rebollo-Mesa I et al.B-lymphocytes support and regulate indirect T-cell alloreactivity in individual patients with chronic antibody-mediated rejection.Kidney Int. 2015; 88: 560-568Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar These results suggested that recipient B cells were involved in allospecific MHC-restricted responses in the early phase of rejection, although the cellular mechanism remains unclear since recipient B cells are not infiltrating the transplant, at least during the initial phase of transplantation when adaptive allo-immunity is triggered. G. Lombardi’s team went further in deciphering allospecific MHC presentation by B cells in their model where the main rejection mechanism is indirect presentation. They demonstrated that recipient B cells were able to acquire both intact MHC class I and II molecules loaded with class I-derived peptides via extracellular vesicule (EVs) transfer in SLO, probably in a nonantigen-specific fashion. Recipient B cells “cross-dressed” with donor EVs activated donor-specific CD4+ T cells with indirect specificities. Those results are similar to those of 2 studies where EVs derived from donor DCs were identified as the main actors of adaptive allo-immunity, which is triggered in SLO.3Liu Q Rojas-Canales DM Divito SJ et al.Donor dendritic cell-derived exosomes promote allograft-targeting immune response.J Clin Invest. 2016; 126: 2805-2820Crossref PubMed Scopus (194) Google Scholar,4Marino J Babiker-Mohamed MH Crosby-Bertorini P et al.Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation.Sci Immunol. 2016; 1: aaf8759Crossref PubMed Scopus (120) Google Scholar Lui et al demonstrated in a murine model of heart transplantation that few donor DCs migrated to SLO, though they were the main source of donor-derived EVs that “cross-dressed” recipient DCs and allowed them to activate allo-reactive CD4+ T cells. Similarly, Mariano et al observed in a murine model of mismatched skin, heart, and islet transplantation that a very small proportion of donor leukocytes trafficked to SLO (100 per 106). They demonstrated that a high proportion of recipient leukocytes (mostly DCs and B cells) were “cross-dressed” with donor MHC acquired from donor-derived EVs. Those “cross-dressed” leukocytes could initiate adaptive allo-immunity (donor-specific CD4+ T cells). In conclusion, Prof G. Lombardi’s team have demonstrated a new role for recipient B cells as antigen-presenting cells that acquired donor EVs bearing MHC complexes and probably in a non–antigen-dependent fashion. The precise mechanism is still unclear (other receptors? pinocytosis? direct membrane exchange?). These “cross-dressed” B cells were able to induce donor-specific MHC-restricted responses in the early phase of transplantation. These results are challenging canonical “leukocyte passenger theory” where allograft rejection is initiated by donor leukocytes (mostly DCs) migrating to the host’s SLO and interacting with donor-specific recipient T cells.5Larsen CP Austyn JM Morris PJ. The role of graft-derived dendritic leukocytes in the rejection of vascularized organ allografts. Recent findings on the migration and function of dendritic leukocytes after transplantation.Ann Surg. 1990; 212: 308-317Crossref PubMed Google Scholar Prof G. Lombardi highlights a new paradigm in transplant immunopathology where donor DCs and thus direct presentation would not be the main actor in the early phase of rejection. The question is, “Can EVs promote tolerance?” Owen’s observation in 1954 about noninherited maternal antigens (NIMAs) may be relevant with Rh-negative daughters of Rh-positive women less likely to develop Rh antibodies during their pregnancies than Rh-negative daughters of Rh-negative women. Later, Burlingham’s work unraveled the underlying mechanism: microchimerism defined as the presence of a very small fraction of immune cells (1 per 104 to 1 per 106) in the offspring. EVs bearing NIMAs and immunoregulatory molecules such as CTLA4 and PD-L1 could “cross-dress” offspring DCs and promote tolerance to NIMAs.6Bracamonte-Baran W Florentin J Zhou Y et al.Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance.Proc Natl Acad Sci USA. 2017; 114: 1099-1104Crossref PubMed Scopus (43) Google Scholar These results suggest that EVs could be the missing link between microchimerism and acquired tolerance. In the context of organ transplantation, the results from G. Lombardi’s team raise the hypothesis that in the early phase of transplantation, microchimerism (=passenger leukocytes) could promote allospecific long-lasting tolerance through tolerogenic EVs “cross-dressing” recipient antigen-presenting cells (APCs). This question will be addressed by a better understanding of the dynamic homeostasis and interplay of donor EVs and recipient APCs throughout transplant life. This editing was supported in the context of the ANR project BIKET (ANR-17-CE17-0008), the University Hospital Institute (IHU)-European Center for Transplantation and Immunotherapy Services (CESTI), and the LabEX IGO thanks to French government financial support managed by the National Research Agency via the “Investment into the Future” program (ANR-10-IBHU-005 and ANR-11-LABX-0016-01). Luc Colas is under Cifre contract with Glaxo Smith and Kline company and financially supported by Institut de Recherche en Santé Respiratoire des Pays de la Loire (IRSRPL). We also thank Dr Nuala Mooney for reviewing English language. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation." @default.
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• W3048579723 title "B cells and extracellular vesicles: New key players in solid organ transplantation?" @default.
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