Treg Enhancing Therapies to Treat Autoimmune Diseases

Abstract

Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are varied and pleiotropic. The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Irregularities in Treg function and number can result in loss of tolerance and autoimmune disease. Restoring immune homeostasis and tolerance through the promotion, activation or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. Such therapies have focused on the Treg cell subset by using drugs to suppress T effector cells and promote Tregs. Other approaches have trialed inducing tolerance by administering the autoantigen via direct administration, by transient expression using a DNA vector, or by antigen-specific nanoparticles. More recently, cell-based therapies have been developed as an approach to directly or indirectly enhance Treg cell specificity, function and number. This can be achieved indirectly by transfer of tolerogenic dendritic cells, which have the potential to expand antigen-specific Treg cells. Treg cells can be directly administered to treat autoimmune disease by way of polyclonal Tregs or Tregs transduced with a receptor with high affinity for the target autoantigen, such as a high affinity T cell receptor (TCR) or a chimeric antigen receptor (CAR). This review will discuss the strategies being developed to redirect autoimmune responses to a state of immune tolerance, with the aim of the prevention or amelioration of autoimmune disease.

Keywords: Treg; Treg therapy; autoimmune disease; autoimmunity; cell-based therapy.

Figure 1

New therapeutic approaches for autoimmune disease. A variety of cell-based therapies and non-cell-based therapies are currently being explored in the treatment and prevention of autoimmune diseases. There are cell-based therapies, such as ex vivo-expanded polyclonal Tregs or Tregs transduced with an autoantigen-specific T cell receptor (TCR), chimeric antigen receptor (CAR), or other chimeric receptors such as peptide-MHC. Another cell-based approach utilises the immune-regulating effects of tolerogenic dendritic cells (DC). Faecal transplantation of specific Treg-promoting bacteria may also be beneficial. Non-cell-based therapies include biologicals such as low-dose IL-2 therapy, TNF receptor 2 (TNFR2) agonist therapy and the anti-CD20 antibody rituximab. Drugs, such as rapamycin, can also promote Treg proliferation. Administration of the autoantigen by various methods can vaccinate against autoimmunity. Finally, a combination of such therapies may be more efficacious than one therapy alone.

Figure 2

Mechanisms of action in Treg therapy. Tregs as a cell-based therapy work in many ways to restore immune tolerance. They secrete anti-inflammatory regulatory cytokines, such as IL-10, IL-35 and TGF-beta, which promote the induction of Tconvs into iTregs and the tolerization of dendritic cells (DC) to tolerogenic DCs. Tregs act as a sink for IL-2 through the cell surface IL-2 receptor, CD25. Tregs can directly kill inflammatory cells, such as Tconvs and B cells, by the secretion of perforin and granzymes. Tregs can suppress autoreactive B cells and autoantibody production, as well as suppressing autoreactive Tconvs. Treg therapy can be non-specific by the use of ex vivo-expanded polyclonal Tregs expressing a natural repertoire of T cell receptors (TCRs). By transducing either an antigen-specific TCR or chimeric antigen receptor (CAR) onto the Treg, the Treg can be redirected to specifically activate and target the auto-antigenic immune response. Such antigen-specific interactions increase the potency of the Treg response mechanisms in response to the autoantigen of interest, as well as promoting a clonally expanded set of transduced Tregs to further curtail autoimmunity.

Figure 3

Dendritic cells (DCs) promote Tregs. Mature DCs have the ability to promote Treg proliferation, which can be directed to be antigen-specific. In turn, Tregs have the ability to tolerize DCs, affording them an immunosuppressive phenotype. Tolerogenic DCs’ immunosuppressive mechanisms include decreased surface expression of MHCII and co-stimulatory molecules CD40, CD80 and CD86, and the secretion of indoleamine 2,3-dioxygenase (IDO), retinoic acid (RA) and anti-inflammatory cytokines IL-10 and TGF-beta, all of which result in tolerogenic DC induction, inhibition of Tconv effector function, Tconv anergy, and iTreg induction.