In the absence of a CD40 signal, B cells are tolerogenic

Abstract

When B cells are deprived of signaling through CD40, they exhibit the ability to induce T cell tolerance. The in vivo administration of anti-gp39 and allogeneic B cells diminished the ability of mice to mount an allogeneic response. Tolerance induction was specific for the haplotype expressed on the allogeneic B cells. Selective allospecific unresponsiveness was induced in the CD8 and CD4 compartments by the administration of anti-gp39 and class II-deficient B cells or class I-deficient B cells, respectively. As predicted by studies with anti-gp39 treatment, diminished allospecific responsiveness was induced by the administration of B cells to mice genetically deficient in gp39. Taken together, these data are consistent with the premise that deprivation of CD40 signaling engenders B cells with enhanced tolerogenicity. These studies provide insights into the tolerogenic capacity of resting B cells and outlines a practical approach to exploit this function.

The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells

“…Longterm cardiac alloengraftment was also achieved in 75% of mice after transient administration of anti-CD154 (versus 0% in the control group) [45], and brief treatment with this antibody after transplantation of allogeneic pancreatic islet cells induced indefinite graft survival in approximately 40% of the treated mice and delayed rejection in the remaining recipients, whereas all of the control mice rejected at day 15 [46]. Furthermore, prior transfusion of the recipients with donor lymphocytes (donor-specific transfusion, DST) along with anti-CD154 lead to long-term islet cell survival in 96% of the mice in this study [46], consistent with the observation that allogeneic B cells are a powerful tolerigen if not activated through CD40 [43,44]. Finally, renal allograft rejection in rhesus monkeys was also prevented out to approximately 100 days by transient administration of anti-CD154, at which time re-treatment with the antibody inhibited the rejection process [47].…”

“…Despite the fact that the injected DCs expressed high levels of MHC Class I, MHC Class II, as well as both B7.1 and B7.2 on their surface, allogeneic helper (cytokine production) and cytotoxic T cell responses were found to be greatly diminished in the CD154-deficient mice [unpublished results]. It is not yet clear whether DCs deprived of CD40 maturation signals are actively tolerigenic toward T cells, as has been described for resting B cells [43,44]. However, these data indicate that CD40/CD154 costimulation that occurs in the context of helper T cell/DC cognate interaction is critical for the acquistion of DC antigen-presenting capabilities.…”

“…For instance, the administration of purified allogeneic CD40-deficient B cells or wild-type allogeneic B cells along with anti-CD154 leads to the induction of allotolerance in the CD4 ϩ and CD8 ϩ T cell compartments of the recipient. However, preactivation of the B cells with LPS, accompanied by the induction of high levels of B7.1 and B7.2, restores normal alloreactive T cell responses in these studies [43,44]. Longterm cardiac alloengraftment was also achieved in 75% of mice after transient administration of anti-CD154 (versus 0% in the control group) [45], and brief treatment with this antibody after transplantation of allogeneic pancreatic islet cells induced indefinite graft survival in approximately 40% of the treated mice and delayed rejection in the remaining recipients, whereas all of the control mice rejected at day 15 [46].…”

Ocular Immune Privilege Promoted by the Presentation of Peptide on Tolerogenic B Cells in the Spleen. II. Evidence for Presentation by Qa-1

“…In other models of tolerance, B cells induce CD8 ϩ suppressor T cells when peptides are presented in the context of the nonclassical class I molecule Qa-1 (10). Coupled with other studies showing that B cells can serve as tolerogenic APC (11)(12)(13)(14)(15)(16), these results suggested that the B cell might present Ag in the ACAID spleen.…”

The CD154-CD40 T Cell Costimulation Pathway Is Required for Host Sensitization of CD8+ T Cells by Skin Grafts Via Direct Antigen Presentation

“…Indeed, treatment with anti-CD154 mAb diminished the response to alloantigen on B cells in vitro (18), whereas immunization with resting B cells from CD154 Ϫ/Ϫ mice induced tolerance to alloantigen (19). Treatment with anti-CD154 mAb blocks both primary and secondary immune responses to T cell-dependent Ags, as well as the development of germinal centers and the generation of memory cells (20).…”