Regulatory T cells in kidney transplant recipients: active players but to what extent?

CD4 CD25 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 T cells expressing IL-2 receptor chain in naı̈ve 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 CD25 subset. With varied efficacies, CD4 CD25 , CD8 CD28 , 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 CD25 T cells may well be different in those two stages. Adoptive transfer experiments, so often used to address the role of CD25 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 role and the relevance of well-established regulatory CD4 CD25 T cell subset in the regulation of alloimmune responses during the maintenance of renal transplants. Unlike in other human studies in which cells from healthy volunteers were employed, they sampled blood lymphocytes from transplant recipients with defined clinical diagnosis of graft function, and focused on allorecognition pathways relevant for regulatory T cells. This is the first clinical report on the putative role of CD4 CD25 T cells in maintaining hyporesponsiveness of recipients’ own T cell repertoire toward the donor-type alloantigen, and on the mechanism of their activation in long-term and stable transplant patients. Both groups used similar ex vivo assays to contrast alloreactivity before and after depletion of the CD4 CD25 subset. Complementary to each other, they measured either direct or indirect alloresponses. Their conclusions imply the important role of indirect rather than direct pathway in alloreactive regulatory T cell function. Salama et al. (10) report on twenty-three renal transplant patients, grouped into two cohorts with or without the history of acute rejection. These patients were chosen on the basis of their low reactivity to the mismatched donor-derived HLA-DR antigen. By employing ELISPOT assay, the authors were able to detect significant increase in the frequency of IFN–producing cells stimulated by donor-derived mismatched HLA-DR peptides, after depletion of the CD25 subset. This increase was alloantigen-specific, as the response to recall mumps antigen was unaffected by CD25 depletion. Significantly, this frequency increase was associated with the history of graft rejection, and the initial status of alloresponses toward the mismatched alloantigen in vitro. In contrary to this “positive” finding, Game et al. (11) in their CD25 depletion experiments failed to detect any changes in the direct alloreactivitiy specific to donor-type alloantigens. By screening twelve stable Correspondence to Dr. Jerzy W. Kupiec-Weglinski, Dumont-UCLA Transplant Center 77-120 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095. Phone: 310-825-4196; Fax: 310-267-2358; Email: [email protected]