Past, Present, and Future of Regulatory T Cell Therapy in Transplantation and Autoimmunity

Abstract

Regulatory T cells (Tregs) are important for the induction and maintenance of peripheral tolerance therefore, they are key in preventing excessive immune responses and autoimmunity. In the last decades, several reports have been focussed on understanding the biology of Tregs and their mechanisms of action. Preclinical studies have demonstrated the ability of Tregs to delay/prevent graft rejection and to control autoimmune responses following adoptive transfer in vivo. Due to these promising results, Tregs have been extensively studied as a potential new tool for the prevention of graft rejection and/or the treatment of autoimmune diseases. Currently, solid organ transplantation remains the treatment of choice for end-stage organ failure. However, chronic rejection and the ensuing side effects of immunosuppressants represent the main limiting factors for organ acceptance and patient survival. Autoimmune disorders are chronic diseases caused by the breakdown of tolerance against self-antigens. This is triggered either by a numerical or functional Treg defect, or by the resistance of effector T cells to suppression. In this scenario, patients receiving high doses of immunosuppressant are left susceptible to life-threatening opportunistic infections and have increased risk of malignancies. In the last 10 years, a few phase I clinical trials aiming to investigate safety and feasibility of Treg-based therapy have been completed and published, whilst an increasing numbers of trials are still ongoing. The first results showed safety and feasibility of Treg therapy and phase II clinical trials are already enrolling. In this review, we describe our understanding of Tregs focussing primarily on their ontogenesis, mechanisms of action and methods used in the clinic for isolation and expansion. Furthermore, we will describe the ongoing studies and the results from the first clinical trials with Tregs in the setting of solid organ transplantation and autoimmune disorders. Finally, we will discuss strategies to further improve the success of Treg therapy.

Keywords: Tregs (regulatory T cells); autoimmunity; cell therapy; clinical trial; transplantation.

Figure 1

Treg suppressive mechanisms. Tregs are able to suppress different cell types by direct and indirect mechanisms. Tregs can produce anti-inflammatory cytokines (IL-10, IL-35, and TGFβ) affecting T cells. In addition, they release perforin and granzyme, which damage target cell membrane leading to apoptosis. They can sequester, by the high expression of CD25, IL-2 from the microenvironment reducing effector T cells proliferation. IL-2 starvation reduces NKs from proliferating and exhibiting effector functions as well. Furthermore, NKs can be directly affected by Tregs in a membrane bound TGF-ß dependent manner. Tregs have been observed to have a direct effect on B-cells via PDL1/PD-1 interaction and DCs via both CTLA-4 and LAG-3. CTLA-4 blocks co-stimulation reducing CD80/CD86 expression and it induces upregulation of IDO. The expression of CD39 on Tregs mediate the conversion to ATP to adenosine and AMP and reduce T effector proliferation. Tregs can also skew monocyte toward M2 macrophages and prevent their differentiation in pro-inflammatory M1 macrophages. They can similarly induce a suppressive phenotype in neutrophils and reduce ILC2 cytokine secretion.