Tregs and transplantation tolerance

Abstract

The induction and maintenance of immune tolerance to transplanted tissues constitute an active process involving multiple mechanisms that work cooperatively to prevent graft rejection. These mechanisms are similar to inherent tolerance toward self antigens and have a requirement for active immunoregulation, largely T cell mediated, that promotes specific unresponsiveness to donor alloantigens. This review outlines our current understanding of the Treg subsets that contribute to allotolerance and the mechanisms by which these cells exert their effects as well as their potential for therapy.

Figure 1

Altering the balance between alloaggressive and Treg subsets. Deletional strategies employed at or around the time of transplant reduce the number of potentially graft destructive T cells and facilitate the action of Treg subsets. During the maintenance phase of tolerance, these Tregs, either naturally occurring or induced, can thus act more efficiently on a greatly reduced number of effector T cells. Cell number, as denoted on the y axis, represents an illustration as to how the relative ratio of effector versus Treg subsets alters during the establishment of transplant tolerance and is not meant for comparison between groups.

Figure 2

Infectious tolerance and linked suppression induced by CD4⁺CD25⁺ Tregs. CD4⁺CD25⁺ Treg cells can suppress alloreactive CD4⁺ T cells either directly via cell contact or secretion of IL-10 and TGF-β or alternatively by influencing the stimulating APC. Linked suppression arises when tolerance generated against a specific antigen (Ag-Y) leads to tolerance against unrelated or third-party antigens (Ag-X and Ag-Z), providing that these unrelated antigens are expressed on the surface of the same APC. The secretion of IL-10 and TGF-β by Tregs has been implicated in this process, which is thought to reinforce the infectious nature of transplant tolerance.