Alloreactive B cells acquire suppressive function in recipients tolerant to allografts

Abstract

Abstract Establishing a state of transplantation tolerance has been achieved in limited numbers of transplant recipients in the clinic. Clinical observations suggest that donor-specific antibodies can mediate allograft rejection, leading us to hypothesize that stable transplantation tolerance requires donor-specific B cell responses to also be suppressed. We hypothesize that this can be achieved through the induction of B cell-intrinsic tolerance. Using a well-established experimental model of transplantation tolerance induced to allogeneic B/c hearts with anti-CD154+donor spleen cell transfusion, we observed that donor-specific B cells are intrinsically tolerant. B cells from tolerant recipients did not produce anti-B/c IgG when adoptively transferred into naïve MD4 host and challenged with B/c splenocytes or heart grafts, and were blocked in their ability to differentiate into germinal center (GC) B cells. To test whether tolerant B cells could be rescued by ongoing GC responses, we adoptively transferred tolerant B cells into congenic hosts, followed by B/c spleen cell immunization. Tolerant B cells did not recover their ability to differentiate into antibody secreting cells, but instead they are able to suppress IgG production by naïve host B cells. Finally, we show that donor-specific tolerant B cells are not able to suppress third-party antibody responses nor exhibit linked suppression. Taken together, our data demonstrate that tolerant donor-specific B cells are profoundly altered compared to naïve B cells: they have significantly diminished ability to differentiate into antibody secreting cells, but instead acquired the ability to suppress donor-specific, but not third-party, antibody responses by naïve B cells.