Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation

Abstract

Regulatory T (Treg) cells are a heterogenous population of immunosuppressive T cells whose therapeutic potential for the treatment of autoimmune diseases and graft rejection is currently being explored. While clinical trial results thus far support the safety and efficacy of adoptive therapies using polyclonal Treg cells, some studies suggest that antigen-specific Treg cells are more potent in regulating and improving immune tolerance in a disease-specific manner. Hence, several approaches to generate and/or expand antigen-specific Treg cells in vitro or in vivo are currently under investigation. However, antigen-specific Treg cell therapies face additional challenges that require further consideration, including the identification of disease-relevant antigens as well as the in vivo stability and migratory behavior of Treg cells following transfer. In this review, we discuss these approaches and the potential limitations and describe prospective strategies to enhance the efficacy of antigen-specific Treg cell treatments in autoimmunity and transplantation.

Keywords: Tregs; antigen-specific Tregs; autoimmune disease (AD); regulatory T cells; therapy; transplantation.

Figure 1

Different approaches of polyclonal and antigen-specific Treg cell-based therapies. To date, two main strategies have been developed: the administration of immunomodulatory agents that enhance the number and/or function of Treg cells in vivo (A, B), and the adoptive transfer of in vitro expanded Treg cells (C, D). Interventions that increase polyclonal endogenous Treg cells in vivo involve low-dose interleukin-2 (IL-2), mutant IL-2, IL2/Anti-IL-2 Ab complexes as well as selective depletion of Teff cells by Anti-CD3 Ab (A). In contrast, applications of antigen-based treatments could lead to the enhancement of antigen-specific Treg subsets (B). On the other hand, adoptive Treg cell therapies rely on the optimal isolation and expansion of Treg cells in vitro. Thus far, clinical trials in autoimmunity have only utilized expanded polyclonal Treg cell populations (C). However, antigen-specific Treg cells can be generated in vitro (D) by genetic insertion of synthetic receptors (including engineered T cell receptors (TCR), chimeric antigen receptors (CAR) or B cell antibody receptors (BAR)), or by transformation of antigen-specific effector T (Teff) cells into induced Treg (iTreg) cells via stimulation in the presence of transforming growth factor beta (TGF-ß) and IL-2, transgenic FOXP3 overexpression, blockade of cyclin-dependent kinase 8 (CDK8) and CDK19 signaling, or a combination of cytotoxic T lymphocyte antigen 4 (CTLA-4) overexpression, IL-2 ablation and antigenic stimulation. The isolation and expansion of endogenous antigen-specific Treg cells remains technically challenging. Ag, antigen; DCs, dendritic cells; APL, altered peptide ligands; pMHC, peptide-major histocompatibility complex.