Ly-6A is critical for the function of double negative regulatory T cells

Abstract

We have recently demonstrated that CD3+CD4–CD8– double negative (DN) T cells can down‐regulate allogeneic immune responses both in vitro and in vivo by killing activated syngeneic CD8+ T cells. The goal of this study was to identify molecules that are crucial for DN T cell‐mediated suppression. We demonstrate that Ly‐6A (Sca‐1) is highly expressed on DN T cells. Incubation with IL‐10 significantly reduced Ly‐6A expression and the function of DN T cells. DN T cell‐mediated killing was significantly reduced when Ly‐6A was blocked.Ly‐6A‐deficient mice showed an accelerated allograft rejection when compared to wild‐type controls. Furthermore we demonstrate that pretransplantation donor lymphocyte infusion (DLI) led to activation and proliferation of recipient DN T cells and prolongation of bm1→B6 skin allograft survival. However, when the recipients were deficient in Ly‐6A, the beneficial effect of DLI on allograftsurvival was abolished. Moreover, deficiency in Ly‐6A did not affect the activation and proliferation of DN T cells. Rather, it impaired the ability of DN T cells to kill activated anti‐donor CD8+ Tcells. Taken together, our data indicate that Ly‐6A plays a crucial role in DN T cell‐mediated regulation in vitro and in vivo, perhaps by enhancing DN‐CD8+ T cell signaling.

Inhibition of Graft-Versus-Host Disease by Double-Negative Regulatory T Cells

“…We have recently demonstrated in three different mouse models that DN T cells have a regulatory function and can suppress immune responses mediated by CD8 ϩ or CD4 ϩ T cells that are syngeneic to the DN T cells (7,8,13,14,29,30). Next, we studied whether DN T cells from reconstituted recipient mice were able to suppress proliferation of syngeneic antihost CD8 ϩ T cells.…”

“…We and others have demonstrated that the infusion of single MHC class I locus-mismatched donor lymphocytes may lead to permanent acceptance of donor-specific skin and heart allografts without the need for nonspecific immunosuppression in H-2K bm1 (7,8)-, H-2K b (9, 10)-, and H-2L d (11)(12)(13)(14)-mismatched mouse models. Likewise, it has been shown that the infusion of recipient cells that have been genetically engineered to express a donor MHC class I molecule can also induce transplantation tolerance (10,15,16).…”

Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

“…We have demonstrated that mouse DN-Treg specifically can eliminate activated syngeneic anti-donor CD4 + T cells, CD8 + T cells, and B cells [22,23,25,26]. Furthermore, adoptive transfer of DN-Treg leads to significant prolongation of donor-specific skin and heart allografts in a single MHC-mismatched murine model [22,23,27].…”

“…In recent studies, we found that TCRab + CD3 + CD4 -CD8 -(double-negative, DN) T cells possess immuneregulatory functions and play an important role in the development of tolerance post-transplantation [22][23][24][25]. We have demonstrated that mouse DN-Treg specifically can eliminate activated syngeneic anti-donor CD4 + T cells, CD8 + T cells, and B cells [22,23,25,26].…”

“…This notion has been well addressed in the hybrid resistance model, in which parental BM cells, not solid organs, are vigorously rejected by an F1 hybrid [10,11]. This rejection is mediated solely by a recipient's NK cells, not by T cells, NKT cells or B cells [12][13][14] [20,21].In recent studies, we found that TCRab + CD3 + CD4 -CD8 -(double-negative, DN) T cells possess immuneregulatory functions and play an important role in the development of tolerance post-transplantation [22][23][24][25]. We have demonstrated that mouse DN-Treg specifically can eliminate activated syngeneic anti-donor CD4 + T cells, CD8 + T cells, and B cells [22,23,25,26].…”