Self-reacting regulatory CD4⁺CD25⁺ T cells play a critical role in the suppression of auto-reactive T cells as well as in the control of innate immunity. They are physiological tools that prevent excesses of immune responses against pathogens and secure homeostasis of the immune system. Nevertheless, their antigen specificity still remains unknown. They can suppress other naïve T cells and make them tolerant to the relevant antigen. Allograft rejection depends on the balance between effector T cells and regulatory T cells. In unmanipulated allograft recipients, alloreactive effector T cell precursors exceed regulatory T cells, automatically tipping the balance toward allograft rejection. Transplanted tissues from allogeneic donors actually share far more identities than disparities with the host. So far, the roles played by these identities in the allograft outcome remain unknown and only little evidence suggests their active role in the allograft acceptance. Sharing identical MHC class II molecules between donor and recipient allows donor cells to present self-peptides that are identical in the host and the recipient. In this way, self-reacting regulatory T cells could mediate linked suppression of anti-donor-specific T cells.

We have recently observed an array of evidence showing that recipient stimulation with self-antigens modulates alloreactive response and suppresses allograft rejection in the absence of any immunosuppressive drug. Self-antigen stimulation was performed either through adjacent syngeneic transplants, the use of semi-allogeneic (donor x recipient) F1 allografts, or injections of lipopolysaccharides (LPS)-activated autologous dendritic cells (DC).

In the present project, we will examine whether or not self-reacting regulatory T cells are involved in these regulation processes, their critical mechanisms as well as their antigen-restriction. We will investigate the promoting or inhibiting effect of classical immunosuppressive drugs. As their rationale is based on homeostatic highly conserved mechanisms, they should be easily adapted to non-human and human primates. They might lead to feasible cell or molecular therapy through recipient DC manipulations and/or repeated heat-shock protein administrations.