Regulation and privilege in transplantation tolerance

Area of Science:

• Immunology
• Transplantation Biology
• T Cell Regulation

Background:

• Non-chimeric tolerance induction in rodents is achievable via antibody blockade of co-receptors (CD4, CD8) or co-stimulatory molecules (CD40L).
• This tolerance is operational, with effector cells remaining but controlled by CD4 regulatory T cells (Treg).
• Both natural and induced CD4(+)CD25(+) FoxP3(+) Treg cells are implicated, functioning within grafts and lymphoid tissues to establish acquired privilege.

Purpose of the Study:

• To elucidate the mechanisms underlying operational transplantation tolerance.
• To investigate the role of regulatory T cells (Treg) in maintaining graft acceptance without chimerism.
• To understand how persistent antigen and microenvironments contribute to long-term graft survival.

Main Methods:

• Rodent models of transplantation tolerance.
• Antibody-mediated blockade of co-receptors and co-stimulatory molecules.
• Analysis of Treg cell populations and function within grafts and lymphoid tissues.

Main Results:

• Operational tolerance is maintained by CD4+ regulatory T cells (Treg) controlling residual effector cells.
• Treg cells are found within tolerated grafts and draining lymphoid tissues, suggesting a role in acquired privilege.
• Linked suppression indicates Treg decommission antigen-presenting cells, promoting further Treg conversion.

Conclusions:

• Regulatory T cells (Treg) are central to operational transplantation tolerance, functioning within microenvironments to suppress rejection.
• Persistent antigen and inhibitory microenvironments facilitate infectious tolerance throughout the recipient's life.
• Transforming growth factor-beta (TGF-beta) appears crucial for inducing Treg function and inhibiting effector responses necessary for rejection.