Abstract
Regulatory T cells (Tregs) are crucial in controlling allospecific immune responses. However, studies in human kidney recipients regarding the contribution of polyspecific Tregs have provided differing results and studies on alloreactive Tregs are missing completely. In this retrospective study, we specifically analyzed activated CD4+CD25highFOXP3+GARP+ Tregs in 17 patients of a living donor kidney transplantation cohort longitudinally over 24 months by flow cytometry (FOXP3: forkhead box protein 3, GARP: glycoprotein A repetitions predominant). We could demonstrate that Tregs of patients with end-stage renal disease (ESRD) are already pre-activated when compared to healthy controls. Furthermore, even though total CD4+CD25highFOXP3+ Treg numbers decreased in the first three months after transplantation, frequency of activated Tregs increased significantly representing up to 40% of all peripheral Tregs. In a cohort of living donor kidney transplantation recipients with stable graft function, frequencies of activated Tregs did not correlate with the occurrence of acute cellular rejection or chronic graft dysfunction. Our results will be important for clinical trials using adoptive Treg therapy after kidney transplantation. Adoptively transferred Tregs could be important to compensate the Treg loss at month 3, while they have to compete within the Treg niche with a large number of activated Tregs.
Highlights
Regulatory T cells (Tregs) play a pivotal role in immune regulation mediating self-tolerance and tolerance to alloantigens by suppressing effector T cells[1]
Studies on circulating Tregs displayed lower numbers of CD4+CD25highFOXP3+ Tregs in chronic rejection, whereas kidney recipients with stable allograft function and operational tolerance had similar Treg frequencies compared to healthy controls[19,20,21,22]
We analyzed the precursor frequencies of alloreactive Tregs in seven healthy volunteers, each being stimulated with 5 different allogeneic Peripheral blood mononuclear cells (PBMC) donors (Fig. 1)
Summary
Regulatory T cells (Tregs) play a pivotal role in immune regulation mediating self-tolerance and tolerance to alloantigens by suppressing effector T cells[1]. Studies on circulating Tregs displayed lower numbers of CD4+CD25highFOXP3+ Tregs in chronic rejection, whereas kidney recipients with stable allograft function and operational tolerance had similar Treg frequencies compared to healthy controls[19,20,21,22]. All of these studies failed to demonstrate superior immunosuppressive potencies of Tregs of tolerant patients after polyclonal stimulation. Our study is the first, analyzing the impact of the allogeneic immune response on the activation level in Tregs after kidney transplantation
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