The role of FOXP3+ regulatory T cells in human autoimmune and inflammatory diseases

Abstract

CD4⁺ regulatory T cells (T_reg ) expressing the forkhead box protein 3 (FOXP3) transcription factor (T_regs ) are instrumental for the prevention of autoimmune diseases. There is increasing evidence that the human T regulatory population is highly heterogeneous in phenotype and function. Numerous studies conducted in human autoimmune diseases have shown that T_reg cells are impaired either in their suppressive function, in number, or both. However, the contribution of the FOXP3⁺ T_reg subpopulations to the development of autoimmunity has not been delineated in detail. Rare genetic disorders that involve deficits in T_reg function can be studied to develop a global idea of the impact of partial or complete deficiency in a specific molecular mechanism involved in T_reg function. In patients with reduced T_reg numbers (but no functional deficiency), the expansion of autologous T_reg cells could be a suitable therapeutic approach: either infusion of in-vitro autologous expanded cells, infusion of interleukin (IL)-2/anti-IL-2 complex, or both. T_reg biology-based therapies may not be suitable in patients with deficits of T_reg function, unless their deficit can be corrected in vivo/in vitro. Finally, it is critical to consider the appropriate stage of autoimmune diseases at which administration of T_reg cellular therapy can be most effective. We discuss conflicting data regarding whether T_reg cells are more effectual at preventing the initiation of autoimmunity, ameliorating disease progression or curing autoimmunity itself.

Keywords: T regulatory cells; Treg; autoimmune; cell therapy; inflammation.

Figure 1

Human regulatory T cell (T_reg) subsets. Thymus produces CD45RA⁺forkhead box protein 3 (FOXP3)^lo naive T_reg (nT_reg) cells as well as naive CD45RA⁺ non‐T_reg cells. nT_reg cells can differentiate into CD45RA^–FOXP3^hi effector T+ (eT_reg) cells, which are potently suppressive, but they can also maintain low levels of FOXP3 and become non‐T_reg cells. Effector T_reg cells can also convert into non‐T_reg cells, while non‐T_reg cells can up‐regulate FOXP3 transiently to become induced effector T_reg cells. As shown, all FOXP3‐expressing subsets can be divided into subsets by differential expression of surface markers or transcription factors.

Figure 2

Relationship between the intensity of regulatory T cell (T_reg) functional deficiency and the severity and time to onset of the disease. By comparing patients with rheumatoid arthritis (RA), cytotoxic T lymphocyte antigen 4 (CTLA‐4) haploinsufficiency, lipopolysaccharide‐responsive and beige‐like anchor protein (LRBA) insufficiency and immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX), we can study the relationship between the intensity of CTLA‐4 related functional deficiency on T_reg cells, the effect on T_reg biology and the extent of any clinical presentation (including its severity and time of onset).

Figure 3

Timing of regulatory T cell (T_reg)‐mediated suppression of immune responses. T_reg cells inhibit the initiation of immune responses by preventing the activation of effector cells. One important mechanism of suppression is their ability to adsorb interleukin (IL)‐2 produced by effector cells (top). When effector cells are preactivated, T_reg cells are not capable of suppressing the ongoing immune responses. In this case, IL‐2 is massively produced and amplifies the activated effector cell pool and also the T_reg cells. They can still suppress some non‐activated cells present in the vicinity by bystander suppression (bottom). Mild beneficial therapeutic effects observed in active diseases treated with T_reg biology‐based therapies can be explained by the absence of suppression of activated immune cells and the prevention of the activation of dormant pathogenic cells.

Figure 4

Therapeutic strategies for autoimmune diseases with regulatory T cell (T_reg) biology‐based treatments. The current gold standard treatment regimen for autoimmune diseases includes an induction phase, which aims to eliminate pathogenic cells. Usually, high‐dose steroids are given intravenously during the first days, followed by oral steroids with a tapering scheme. Immunosuppressants such as cyclophosphamide, mycophenolate or rituximab are also necessary to induce remission. When remission is obtained, it is necessary to maintain mild immunosuppressants such as azathioprine or mycophenolate to prevent the occurrence of subsequent flares or relapses of the disease. In diseases with number deficiency of functional T_reg cells, autologous T_reg cells infusion or interleukin (IL)‐2/anti‐IL‐2 complexes can be used as a maintenance treatment when the disease is controlled by standard induction treatments. In diseases with dysfunctional T_reg cells, if the dysfunctional mechanism of suppression is identified molecules mimicking the T_reg function, genetically corrected autologous T_reg cells or allogeneic or cord blood T_reg cells can be infused as maintenance treatment.