FOXP3+ regulatory T cells: From suppression of rejection to induction of renal allograft tolerance

Naturally occurring and induced regulatory T cells (Tregs) can become hyporesponsive and anergic to antigen stimulation in autoimmune diseases and allograft rejection. The mechanisms of suppression of effector T cells by Tregs remain unclear, but there are in vitro and in vivo evidences showing that these cells are able to suppress antigen-specific responses via direct cell-to-cell contact, secrete anti-inflammatory cytokines such as TGF-beta and IL-10, and inhibit the generation of memory T cells, among others. The transcription factor FOXP3 is a specific marker of Tregs and its deficiency is associated with autoimmune diseases and inflammation. During acute rejection of kidney allografts, an augmented FOXP3 gene expression as well as increased CD4(+)CD25(+)FOXP3(+) and other cell populations are observed in graft biopsies. However, it is not clear whether Tregs migrate into the graft and are retained there to suppress the inflammatory process, or whether they are directly associated with more complex mechanisms to induce immune tolerance. FOXP3(+) Tregs may direct the immune response toward a graft acceptance program, potentially affecting the long-term survival of transplanted organs and tissues. Immunosuppressive drugs modulate the number and function of circulating Tregs and FOXP3 expression. Experimental and clinical studies have shown that mTOR inhibitors have positive and calcineurin inhibitors negative effects on Tregs, but it is difficult to set apart the effect of multiple other factors known to be associated with short- and long-term renal graft outcomes. This review aimed to describe the functions of Tregs and its transcription factor FOXP3 in suppression of immune response during rejection and in induction of kidney graft tolerance, as well as to review the individual effects of immunosuppressive drugs on Tregs. (C) 2011 Elsevier B.V. All rights reserved.