THE ROLE OF FOXP3+ REGULATORY T-CELLS IN TRANSPLANT TOLERANCE

A major conceptual shift in immunology has been the recent discovery of regulatory T-cells (Treg), of which CD4+Foxp3+ cells are already known to be essential to self-tolerance. Their role in transplant tolerance remains unproven due to the absence of a natural cell surface marker by which they can be manipulated in vivo. A transgenic B6.Foxp3hCD2 mouse was created to express an artificial GPI-anchored human CD2/CD52 surface fusion protein under the control of the Foxp3 promoter. Monoclonal antibodies directed against the human CD2 and human CD52 were used in B6.Foxp3hCD2 mice to isolate and ablate Foxp3+ Treg. CD4+Foxp3+ cells were found to be crucial for transplant tolerance induced by non-ablative co-receptor and co-stimulatory blockade. In tolerant animals, Foxp3+ Treg are constantly required to suppress effector T-cells still capable of causing tissue damage. Remarkably, tolerated tissue contains T-cells capable of rejecting it, but these are prevented from doing so by therapeutically induced Foxp3+ Treg. Finally, induced Foxp3+ cells sustain tolerance by converting naive T-cells into the next generation of Foxp3+ cells in the periphery, providing one potential mechanism by which infectious tolerance may operate in vivo.