Regulatory T Cells in Kidney Transplant Recipients

Abstract

CD4 ϩ CD25 ϩ T cells are now well established as naturally occurring immune regulatory T cells. Resurrected from the suppressor T cell adversity, Sakaguchi et al. (1) showed in mid-1990 that a subset of CD4 ϩ T cells expressing IL-2 receptor ␣ chain in naïve animals had the ability to control autoreactive T cells in vivo. These T cells were not only hyporesponsive to antigenic stimulation but also suppressive to other otherwise responsive T cells via cell-cell contact mechanism. Although originally identified in the mouse system, it is now clear that a T cell population with the same phenotypic and functional properties does exist in humans (2). These T cells are crucial in preventing various forms of autoimmune diseases, which makes them a key regulatory element in maintaining self-tolerance. This raises an obvious question regarding the role regulatory T cells may play in allograft tolerance. Although still an elusive goal in clinical transplantation, immunologic tolerance against MHC-incompatible organ allografts is now readily inducible in a number of murine and some primate transplant models (3,4). In addition, few human studies have reported rejection-free states in the absence of immunosuppression (5-7). Importantly, immunologic tolerance does not mean complete unresponsiveness toward the graft, but rather a lack of destructive immune response against it in the face of generalized immune competence (8). Multiple tolerogenic mechanisms, including depletion, anergy, and immune regulation operate in different forms or combinations depending on the animal model and immunosuppression. The role of immune regulation is of particular interest and under intensive study nowadays. Different from the case of autoimmune diseases, regulatory T cells involved in transplantation tolerance are not limited to the CD4 ϩ CD25 ϩ subset. With varied efficacies, CD4 ϩ CD25 Ϫ , CD8 ϩ CD28 Ϫ , NK, or DN T cells have been all shown to exert regulatory functions in allografted hosts (9). Two distinctive and dynamic stages can be envisioned during the acquisition of tolerance in adult transplant recipients: the induction and maintenance phases. The immune regulation is the only active mechanism capable to control coexisting alloreactive T cells (i.e., those that escaped deletion or are continuously produced in the thymus) in immunocompetent recipients. The role of distinct types of regulatory T cells, or CD4 ϩ CD25 ϩ T cells may well be different in those two stages. Adoptive transfer experiments, so often used to address the role of CD25 ϩ T cells in murine models, do not mimic the real physiologic situation in reference to the immunologic environment (e.g., ratios of effector:regulatory T cells), and their results primarily reflect the function of regulatory T cells in the induction phase. Indeed, no reliable models to probe the role of regulatory T cells in the maintenance of tolerance have been established.The articles by Salama et al. (10) and Game et al. (11) in this issue of JASN pioneer the clinical effort to study the ro...

Donor Antigen and Transplant Tolerance Strategies

“…However, it is likely that (LEW ϫ AUG)F1 DC are more efficient than recipient (LEW) DC at presenting AUG antigen to LEW T cells, given the high levels of MHC-derived peptides that occupy MHC class II molecule peptide binding grooves (25), which may translate into more powerful indirect regulatory T cell induction. Interestingly, in recent reports published in JASN, regulatory T cells were found to play an important role in mediating indirect (26) but not direct (27) pathway hyporesponsiveness in renal transplant recipients (28).…”