Regulatory T cells after organ transplantation: Where does their action take place?
Introduction
Transplantation of organs has become a rapidly evolving therapy for end-stage organ failure. Unfortunately, clinical success has been limited by the ongoing need for immunosuppressive therapy that reduces the risk of allograft rejection but also carries unwanted side effects, such as the increased susceptibility to infection and malignancy [1]. Moreover, although immunosuppressive drugs efficiently inhibit acute allograft rejection, a substantial proportion of patients experience chronic rejection that ultimately leads to functional loss of the graft [2]. Thus immunosuppressive therapy is not sufficient to inhibit all immune responses directed to the transplanted organ. An alternative approach to avoid rejection and, subsequently, the need for life-long treatment with immunosuppressive drugs is the induction of tolerance to donor allografts. The identification and characterization of regulatory T cells that control immune responses to self-antigens and non–self-antigens, and thus may play a relevant role in the induction and persistence of tolerance toward a transplanted organ, has become the focus of many studies. Although much has been written about the possible role of regulatory T cells in transplantation tolerance [3], [4], the exact compartments in which these cells interact with allogeneic effector T cells and antigen-presenting cells (APCs) remain unclear. As the localization of regulatory T-cell activity may influence its effect on allogeneic responses, knowledge of the sites of action is important, especially if regulatory T cells are to be used for monitoring purposes and cellular immune therapy. In this review, we will first describe various regulatory T-cell populations that may play a pivotal role in the induction of nonresponsiveness to donor antigens, and we will then discuss their possible sites of action.
Section snippets
Regulatory T-cell populations
One of the first studies that described a CD4+ T-cell population with suppressive capacities was published in 1990. Hall et al. demonstrated in experimental animal models that CD4+ suppressor cells that expressed the interleukin (IL)-2 receptor α chain (CD25) were able to inhibit cardiac allograft rejection [5]. Some years later, Sakaguchi et al. showed that a small subset of CD4+ T cells that constitutively express CD25 was important for the prevention of autoimmune diseases [6]. Ever since,
Immune regulation: Where does the action take place?
Close contact of regulatory T cells with effector cells, either directly or through an APC intermediate, is essential for exerting their regulatory function [41]. Thus, active suppression of anti-donor immune reactivity can only occur when migration and homing of regulatory T cells run parallel to that of donor-reactive cells, so that these cells can localize together at the sites of immune activity. The dynamics of donor-reactive cells are schematically depicted in Figure 1A. T cells can be
Secondary lymphoid organs
To inhibit the priming of naive alloreactive T cells, regulatory T cells should be able to home into the secondary lymphoid organs. Indeed, CD4+CD25+ regulatory T cells express CD62L, a cell adhesion molecule required for constitutive migration of lymphocytes through secondary lymphoid organs, and CCR7, a chemokine that mediates homing into the secondary lymphoid tissues [15]. Moreover, it has been shown that homing of CD4+CD25+ regulatory T cells into the lymph nodes is required for the
Peripheral blood
After activation and differentiation, effector T cells migrate from the secondary lymphoid tissues via the blood system to the site of inflammation, which, in the case of organ transplantation, is the transplanted allograft. From the viewpoint of immune tolerance, it would be beneficial for regulatory T cells to have the same migration features as those of donor-reactive effector T cells to exactly follow them from the secondary lymphoid tissues in the peripheral blood and suppress them before
Transplanted organ
The main target of alloantigen-activated T cells is the transplanted organ, so as to eliminate the foreign antigens. Our group demonstrated in heart transplant patients that cytotoxic CD8+ and CD4+ T cells with high avidity for donor antigens home in the graft to induce transplant rejection [65], [66]. For effector-cell recruitment, experimental data point to the chemokine receptors CXCR3 and CCR5, which are induced upon activation of T cells, as key mediators in response to the local
Conclusions
Experimental animal studies have demonstrated that regulatory T cells with the potential to suppress an anti-donor immune response are present in both secondary lymphoid organs and the transplanted organ itself, indicating that immune regulation may occur at several sites. Likewise, in human transplant recipients, evidence of the presence of potent regulatory T cells in different compartments is rising. Yet differences in accumulation in these compartments found between immunologic quiescence
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