title: Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents.
abstract: Emerging knowledge regarding B cells in organ transplantation has demonstrated that these cells can no longer be taken as mere generators of deleterious Abs but can also act as beneficial players. We previously demonstrated in a rat model of cardiac allograft tolerance induced by short-term immunosuppression an accumulation in the blood of B cells overexpressing inhibitory molecules, a phenotype also observed in the blood of patients that spontaneously develop graft tolerance. In this study, we demonstrated the presence in the spleen of regulatory B cells enriched in the CD24(int)CD38(+)CD27(+)IgD(-)IgM(+/low) subpopulation, which are able to transfer donor-specific tolerance via IL-10 and TGF-β1-dependent mechanisms and to suppress in vitro TNF-α secretion. Following anti-CD40 stimulation, IgD(-)IgM(+/low) B cells were blocked in their plasma cell differentiation pathway, maintained high expression of the inhibitory molecules CD23 and Bank1, and upregulated Granzyme B and Irf4, two molecules described as highly expressed by regulatory B cells. Interestingly, these B cells recognized specifically a dominant donor Ag, suggesting restricted specificity that could lead to a particular B cell response. Regulatory B cells were not required for induction of tolerance and appeared following Foxp3(+)CD4(+)CD25(+) regulatory T cells, suggesting cooperation with regulatory T cells for their expansion. Nevertheless, following transfer to new recipients, these B cells migrated to the allograft, kept their regulatory profile, and promoted local accumulation of Foxp3(+)CD4(+)CD25(+) regulatory T cells. Mechanisms of regulatory B cells and their cell therapy potential are important to decipher in experimental models to pave the way for future developments in the clinic.
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Durand
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Huchet
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Merieau
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Usal
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Chesneau
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Severine
authors.initials: S
authors.lastname: Remy
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Michele
authors.initials: M
authors.lastname: Heslan
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: Cuturi
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
authors.affiliation: INSERM, Unité 1064, 44000 Nantes, France; Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Centre Hospitalier Universitaire de Nantes, 44000 Nantes, France; and Faculté de Médecine, Université de Nantes, 44000 Nantes, France Elise.Chiffoleau@univ-nantes.fr.
authors.forename: Elise
authors.initials: E
authors.lastname: Chiffoleau
mesh_terms: D064591:Allografts; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D060151:B-Lymphocytes, Regulatory / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D053804:Granzymes / Q000276:immunology*; D016027:Heart Transplantation; D007519:Isoantigens / Q000276:immunology; D008297:Male; D010950:Plasma Cells / Q000276:immunology*; D051381:Rats; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D023001:Transplantation Tolerance
chemical_list: D015703:Antigens, CD; D019013:CD40 Antigens; D016207:Cytokines; D007519:Isoantigens; D053804:Granzymes; C509215:Gzmb protein, rat