Donor double-negative Treg promote allogeneic mixed chimerism and tolerance

Area of Science:

• Immunology
• Transplantation Biology
• Cellular Immunology

Background:

• Allogeneic bone marrow (BM) transplantation is crucial for tolerance induction but faces challenges like graft-versus-host disease and graft rejection.
• Natural Killer (NK) cells, in addition to T cells, can mediate BM rejection, posing a significant barrier to successful engraftment.
• Donor-derived NK cell tolerance is essential for long-term mixed chimerism after BM transplantation.

Purpose of the Study:

• To investigate the role of a novel type of regulatory T cell (Treg) with a double-negative (DN) phenotype (TCRalphabeta+CD3+CD4-CD8-) in suppressing NK cell-mediated allogeneic BM graft rejection.
• To explore the potential of DN-Treg as a therapeutic strategy to enhance BM transplantation outcomes.

Main Methods:

• Utilized parent-to-F1 and fully MHC-mismatched BM transplantation models in mice.
• Characterized the phenotype of the novel regulatory T cell population as TCRalphabeta+CD3+CD4-CD8- (DN-Treg).
• Assessed the suppressive function of DN-Treg on NK cell activity and BM graft rejection, examining the roles of perforin and FasL.

Main Results:

• Donor-derived DN-Treg effectively suppressed NK cell-mediated allogeneic BM graft rejection in both tested transplantation models.
• Perforin and FasL expressed by DN-Treg were identified as key mediators in the suppression of NK cell activity.
• Adoptive transfer of DN-Treg promoted stable mixed chimerism and donor-specific tolerance without inducing graft-versus-host disease.

Conclusions:

• Double-negative regulatory T cells (DN-Treg) represent a promising approach to control innate immune responses, specifically NK cell activity, in allogeneic BM transplantation.
• DN-Treg therapy can overcome NK cell-mediated rejection barriers, leading to improved BM engraftment and donor-specific tolerance.
• This study highlights DN-Treg as a potential therapeutic target for enhancing the efficacy and safety of BM transplantation.