The Therapeutic Potential of Regulatory T Cells: Challenges and Opportunities

Abstract

Regulatory T cells (Tregs) are an immunosuppressive subgroup of CD4⁺ T cells which are identified by the expression of forkhead box protein P3 (Foxp3). The modulation capacity of these immune cells holds an important role in both transplantation and the development of autoimmune diseases. These cells are the main mediators of self-tolerance and are essential for avoiding excessive immune reactions. Tregs play a key role in the induction of peripheral tolerance that can prevent autoimmunity, by protecting self-reactive lymphocytes from the immune reaction. In contrast to autoimmune responses, tumor cells exploit Tregs in order to prevent immune cell recognition and anti-tumor immune response during the carcinogenesis process. Recently, numerous studies have focused on unraveling the biological functions and principles of Tregs and their primary suppressive mechanisms. Due to the promising and outstanding results, Tregs have been widely investigated as an alternative tool in preventing graft rejection and treating autoimmune diseases. On the other hand, targeting Tregs for the purpose of improving cancer immunotherapy is being intensively evaluated as a desirable and effective method. The purpose of this review is to point out the characteristic function and therapeutic potential of Tregs in regulatory immune mechanisms in transplantation tolerance, autoimmune diseases, cancer therapy, and also to discuss that how the manipulation of these mechanisms may increase the therapeutic options.

Keywords: autoimmune disorders; cancer; clinical trial; induced regulatory T cells; natural regulatory T cells; regulatory T cells; transplantation.

Figure 1

Two major models for thymus-derived Treg (tTreg) development. (A) The instructive model: Based on this model, the level of TCR stimulation determines the fate of thymocytes. The cells negative selection and maturation to conventional T cells are induced by the stimulation of TCR at high and low levels, respectively. Whereas, the intermediate stimulation of TCR contributes to FoxP3 gene expression. (B) The stochastic or selective model: In this model the induction of FoxP3 gene expression is independent from the strength of TCR signaling and occurs in a CD4^-CD8^- double negative (DN) stage. Therefore, the development of two major groups of T cells (FoxP3⁺ and FoxP3⁻) occurs in the thymus. The FoxP3⁺ cells, with strong reactivity with self-antigens are high resistance to negative selection, and therefore develop into Tregs.

Figure 2

Peripherally-derived Treg (pTregs) development. pTregs can preferentially differentiate from FoxP3⁻ CD4⁺ T cells in the periphery and convert to FoxP3⁺ cells. pTreg differentiation can take place in a long-lasting infection, sub-immunogenic conditions and in the maintenance of gut homeostasis. In addition, two types of FoxP3⁻ have been defined as Tr1 and Th3, which are characterized by their cytokine profiles producing high levels of IL-10 and TGF-β, respectively. IL-10, Interleukin-10; TGF, transforming growth factor.

Figure 3

Cell-mediated suppression mechanisms of Tregs. A variety of molecular mechanisms might operate in a complementary fashion to contribute to Treg-mediated suppression. Tregs exert these suppressive effects on different cell types mainly via three mechanisms: 1) Producing soluble factors such as anti-inflammatory cytokines (IL-10, IL-35, and TGF-β), FLG-2, adenosine, granzyme and perforin. 2) Competing for growth factors: high-affinity CD25 receptors on Tregs and effector T cells compete for the relating ligands.3) Inhibitory receptors: Tregs have been observed to have a direct effect on target cells via interaction of CTLA-4, TIM-3, NRP-1, Gal-1 and LAG-3 and their ligands. CTLA-4, cytotoxic T lymphocyte-associated antigen-4; DC, dendritic cell; FLG-2, fibrinogen-like protein-2; GAL-1, Galectin-1; LAG3, lymphocyte activation gene 3; TGF, transforming growth factor; Treg , regulatory T cell; Teff, effector T cells; TIM-3, T cell immunoglobulin and mucin domain 3; Th17, T helper17; Nrp-1, Neuropilin; MQ, macrophage; IL-2, Interleukin-2; IL-6, Interleukin-6; IL-10, Interleukin-10; IL-35, Interleukin-35.

Figure 4

CD39 and CD73 cooperation as a Treg inhibitory mechanism. The cooperation between CD39 and CD73 as the powerful inhibitory mechanisms of Tregs. CD39, hydrolyses ATP to AMP and CD73 dephosphorylates the product of CD39, turning AMP into adenosine. Adenosine by means of the processes drives a shift from ATP-driven pro-inflammatory immune cell activity to an anti-inflammatory state.

Figure 5

Inhibitory receptors expressed on Tregs. Treg inhibitory effects are mediated by several major receptors such as, CTLA-4, LAG-3, Tim-3, CD39/CD73, NRP-1 and Gal-3. CTLA-4, cytotoxic T lymphocyte-associated antigen-4; GAL-3, Galectin-3 ; LAG3, lymphocyte activation gene 3; TIM-3, T cell immunoglobulin and mucin domain 3; Nrp-1, Neuropilin.

Figure 6

Treg-targeted therapeutic strategies in cancer treatment. The schematic drawing of the three major mechanisms in tumor treatment via targeting Tregs; (A) Treg depletion via anti-CD25 monoclonal antibody (Daclizumab) and an IL-2: diphtheria toxin fusion protein (Denileukin Diftitox). (B) Disruption of Tregs infiltration to the tumor site via KW0761/Mogamulizumab. (C) Suppression of Treg function via Ipilimumab, Tremelimumab, Pembrolizumab, Nivolumab and Anti- GITR. All of these strategies resulted in diminution of the immunosuppressive effects of Tregs in the tumor site (as mentioned in the text).