Current status and perspectives of regulatory T cell-based therapy

Abstract

The CD4⁺FOXP3⁺ regulatory T (Treg) cells are essential for maintaining immune homeostasis in healthy individuals. Results from clinical trials of Treg cell-based therapies in patients with graft versus host disease (GVHD), type 1 diabetes (T1D), liver transplantation, and kidney transplantation have demonstrated that adoptive transfer of Treg cells is emerging as a promising strategy to promote immune tolerance. Here we provide an overview of recent progresses and current challenges of Treg cell-based therapies. We summarize the completed and ongoing clinical trials with human Treg cells. Notably, a few of the chimeric antigen receptor (CAR)-Treg cell therapies are currently undergoing clinical trials. Meanwhile, we describe the new strategies for engineering Treg cells used in preclinical studies. Finally, we envision that the use of novel synthetic receptors, metabolic regulators, combined therapies, and in vivo generated antigen-specific or engineered Treg cells through the delivery of modified mRNA and CRISPR-based gene editing will further promote the advances of next-generation Treg cell therapies.

Introduction

The adaptive immune system can recognize and eliminate pathogens while maintaining the state of unresponsiveness toward self-tissues (Ferreira et al., 2019). This state is termed as immune tolerance, controlled by multiple regulators. Treg cells, a small subset of CD4⁺ T lymphocytes with immunosuppressive function, are identified as the main cell type responsible for T cell-mediated immune tolerance (Sakaguchi et al., 1995). In addition to maintaining immune tolerance, Treg cells also perform specialized functions in tissue homeostasis and repair (Panduro et al., 2016). Functional or numerical defects of Treg cells have been described in many autoimmune diseases (Miyara et al., 2011; Dominguez-Villar and Hafler, 2018). Adoptive transfer of Treg cells is emerging as an attractive therapeutic candidate, which can restore immune tolerance in autoimmune diseases and induce tolerance to allogeneic cells/tissues in transplantation. Completed clinical trials in patients with T1D (Bluestone et al., 2015; Dong et al., 2021), liver transplantation (Levitsky et al., 2009), kidney transplantation (Roemhild et al., 2020; Sawitzki et al., 2020), and GVHD (Brunstein et al., 2011; MacMillan et al., 2021; Pierini et al., 2021), have indicated the feasibility, safety, and efficacy of Treg cell therapies. More ongoing clinical trials will continue to validate their therapeutic potential.

Treg cells are characterized by the high expression of forkhead box protein 3 (FOXP3) and CD25. In addition to CD4⁺FOXP3⁺ Treg cells, CD4⁺FOXP3⁻ type 1 Treg (Tr1) cells can also exert immunosuppressive function through the production of IL-10 and granzyme B, as well as through surface molecules (Song et al., 2021). Type 3 T helper (Th3) cells also mediate suppressive activity via secreting high levels of transforming growth factor-β (TGF-β) (Chen et al., 1994). CD4⁺ FOXP3⁺ Treg cells are the most frequently used in clinical trials of Treg cell therapies to restore or induce immune tolerance. In this Review, we focus on the therapeutic potential of CD4⁺FOXP3⁺ Treg cells. Here, we introduce the current knowledge regarding the biology of Treg cells. We review the cell sources and procedures of Treg cell therapies used in clinical trials. Meanwhile, we summarize new efforts in Treg cell therapies to improve efficacy and durability. These endeavors include transductions of TCR, TRuC, and CAR, and the use of metabolic regulators. Finally, we describe design strategies and perspectives of next-generation engineered Treg cells through the use of novel synthetic receptors, modified mRNA, and CRISPR-based gene editing.