Inducing and Administering Tregs to Treat Human Disease

Abstract

Regulatory T cells (Tregs) control unwanted immune responses, including those that mediate tolerance to self as well as to foreign antigens. Their mechanisms of action include direct and indirect effects on effector T cells and important functions in tissue repair and homeostasis. Tregs express a number of cell surface markers and transcriptional factors that have been instrumental in defining their origins and potentially their function. A number of immune therapies, such as rapamycin, IL-2, and anti-T cell antibodies, are able to induce Tregs and are being tested for their efficacy in diverse clinical settings with exciting preliminary results. However, a balance exists with the use of some, such as IL-2, that may have effects on unwanted populations as well as promoting expansion and survival of Tregs requiring careful selection of dose for clinical use. The use of cell surface markers has enabled investigators to isolate and expand ex vivo Tregs more than 500-fold routinely. Clinical trials have begun, administering these expanded Tregs to patients as a means of suppressing autoimmune and alloimmune responses and potentially inducing immune tolerance. Studies in the future are likely to build on these initial technical achievements and use combinations of agents to improve the survival and functional capacity of Tregs.

Keywords: T regulatory cells; autoimmunity; cellular therapy; immune therapy; immune tolerance.

Figure 1

Current and potential future therapies to promote Tregs and immune tolerance. Therapies, such as rapamycin, anti-CD3 mAb, anti-thymocyte globulin (ATG), and Alefacept, a CD2 binding fusion molecule that eradicates CD2 expressing cells, exert their immune suppressive effect by eliminating effector T cells (gray cell) and tipping the balance in favor of Treg function and/or frequency. In addition, the anti-T cell receptor therapies, such as anti-CD3 mAbs may enhance survival and function of Tregs (yellow). IL-2, signaling through the ILR receptor (purple) and pSTAT5 (orange), is central to Treg survival and FOXP3 maintenance through the signaling cascades shown. FOXP3 inhibits cytokine gene expression by inhibiting NFATc2, as well as other transcriptional factors, such as NFκB and AML1/RUNX1. FOXP3 also facilitates Treg development by amplifying and stabilizing its own expression and inhibiting transcription factors required for other cell lineages, such as Tbet, GATA3, and RORγt. Cell-based therapies include use of Tregs engineered to express TCRs directed against specific antigens, including chimeric antigen receptors (CAR) (blue).