Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

Abstract

Bone marrow (BM) transplantation is an efficient approach to develop donor-specific tolerance and prevent chronic rejection. Allogeneic BM transplantation is limited by donor T cell-mediated graft-versus-host disease, requirement of cytoreduction and high numbers of BM cells. In addition of these drawbacks, recent studies demonstrate that not only T cells, but also NK cells can mediate BM rejection, and long-term mixed chimerism depends on NK cell tolerance. Thus, NK cell is another potential barrier against engraftment of BM and an important target in efforts to induce transplant tolerance. We have previously identified a novel type of Treg with the phenotype TCRab + CD3 + CD4 -CD8 -(double-negative, DN). We and others have demonstrated that DN-Treg can effectively suppress anti-donor T cell responses. In this study, we found that donor-derived DN-Treg can suppress NK cell-mediated allogeneic BM graft rejection in both parent-to-F1 and fully MHC-mismatched BM transplantation models. Perforin and FasL in DN-Treg play important roles in the suppression of NK cells. Furthermore, adoptive transfer of DN-Treg can promote a stable mixed chimerism and donor-specific tolerance without inducing graft-versus-host disease. These results demonstrate a potential approach to control innate immune responses and promote allogeneic BM engraftment. IntroductionEstablishing donor-specific transplant tolerance is beneficial for several reasons: it can prevent chronic rejection and avoid side effects related to long-term immunosuppressive drug treatment. It also can help patients to preserve their own natural immunity against infections and tumors. Achieving mixed chimerism via BM transplantation is an efficient approach that directs the immune system to regard the donor as 'self'. By generating specific immunologic tolerance to donor transplants, chronic rejection as well as the need for ongoing immunosuppression can be avoided [1][2][3].Rejection of MHC-mismatched allografts is largely mediated by a recipient's CD4 + and CD8 + T cells. Recent studies, however, have demonstrated that NK cells are another potential barrier in allograft rejection and tolerance [4][5][6][7]. Furthermore, studies have shown that NK cells can mediate BM rejection [8,9]. 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]. Furthermore, adoptive transfer of DN-Treg leads to significant prolongation of donor-specific skin and heart allografts in a single MHC-mis...

Advances on Non-CD4 + Foxp3+ T Regulatory Cells

“…Subsequent studies reported that DN Tregs displayed antigen specific suppressive activity both in vitro and in vivo (51). DN Tregs not only suppress CD8+ T cell responses, but also inhibit CD4+ T cells (57), B cells (58), NK cells (59), and dendritic cells (DC) (60). …”

“…As might be expected, anti-donor IgM and IgG antibody titers were significantly diminished in recipients of adoptively transferred DN Tregs (58). In a model of murine allogenic bone marrow transfer, DN Tregs supported graft survival through suppressing NK cells by perforin and Fas-FasL dependent pathways (59). …”

“…DN Tregs have been shown to enhance the survival of skin (51, 55, 57), pancreatic islet (55, 68), and heart allografts (65, 69, 70) and heart xenografts (58, 71) and hematopoietic stem cell allografts (59, 67) (Table 3). …”

Immunoregulatory CD4-CD8- T cells as a potential therapeutic tool for transplantation, autoimmunity, and cancer

“…Indeed, TCR transgenic and non-transgenic DN T cells can also inhibit NK cells (He et al, 2007; Su et al, 2012), B cells (Zhang et al, 2006; Hillhouse et al, 2010; Ford McIntyre et al, 2011), and dendritic cells (Gao et al, 2011). The combination of their distinct phenotypic characteristics and their unique antigen-specific immunoregulatory properties toward multiple cellular targets has prompted investigators to examine the role of DN T cells in various disease models.…”

The Mouse Idd2 Locus Is Linked to the Proportion of Immunoregulatory Double-Negative T Cells, a Trait Associated with Autoimmune Diabetes Resistance

“…Indeed, regulatory DN T cells have been shown to promote allograft and xenograft tolerance (12)(13)(14)(15)(16)(17), limit the incidence of graft versus host disease (17)(18)(19)(20), as well as provide resistance to autoimmune diabetes development in different animal models (21)(22)(23). Specifically, autoimmune-prone mice carry fewer DN T cells, and injection of DN T cells has been shown to be sufficient to reduce the incidence of autoimmune diabetes in two distinct TCR transgenic mouse models (21,22).…”