Tolerance Induction in Presensitized Bone Marrow Recipients by Veto CTLs: Effective Deletion of Host Anti-Donor Memory Effector Cells

Abstract

Veto cells have been defined as cells capable of inducing apoptosis of effector CD8 cells recognizing their disparate MHC Ags. Tolerance induced by donor-type veto cells is desirable, because it is restricted to depletion of anti-donor clones without depletion of other immune specificities. It has been shown that anti-third party CTLs exhibit marked veto activity with reduced capacity to induce graft-vs-host disease, when tested on naive effector cells. However, presensitized T cells could play an important role in graft rejection, and therefore, their sensitivity to veto cells could be critical to the implementation of the latter cells in bone marrow transplantation. To address this question, we compared naive and presensitized TCR transgenic effector CD8 T cells, bearing a TCR against H-2d. Both cell types exhibited similar predisposition to killing by veto CTLs in vitro, and this killing was dependent in both cell types on Fas-FasL signaling as shown by using Fas-deficient CD8 T cells from (lprx2c) F1 mice. When tested in a stringent mouse model, in which bone marrow rejection is mediated by adoptively transferred host type T cells into lethally irradiated recipients, veto CTLs were equally effective in overcoming rejection of naive or presensitized host T cells.

Inhibition of Alloantigen‐Primed Memory CD4+ and CD8+ T Cells by Hematopoietic Chimerism in Mice

“…3C). Other researchers found chimerism can inhibit activation of B cells in the primed response [25] and delete mature donor-reactive B cells [26]. Therefore, part of the tolerance induced by the chimerism in our study perhaps was attributed to inhibition of memory T cell stimulation of B cells.…”

Targeting T-cell memory: where do we stand?

“…Expanding these early findings, recent studies showed that CD8 þ CTLs reactive to nonhost alloantigens (anti-third party CTLs) can promote engraftment of allogeneic bone marrow in conjunction with rapamycin treatment [40]. This approach is equally effective in preventing bone marrow allograft rejection mediated by presensitized host memory T cells [41 ]. In-vitro experiments suggested that graft prolongation was achieved because of Fas-mediated deletion of donor-reactive memory T cells, but the exact mechanisms behind these observations remain to be determined.…”

Induction of tolerance in organ recipients by hematopoietic stem cell transplantation

“…Moreover, naturally occurring CD4+CD25+ regulatory T cells, which are required for transplantation tolerance in many model systems [52,53], fail to interfere with allograft rejection mediated by memory T cells, as opposed to their ability to modulate and tolerize naive T cells [54]. In contrast, the anti 3rd-party veto CTLs were recently shown to be equally effective in overcoming rejection mediated either by naive or by memory host T cells, both in-vitro and in vivo [55]. Therefore, veto CTLs are likely excellent candidates for tolerance induction in humans.…”