Gene Therapy With Regulatory T Cells: A Beneficial Alliance

Abstract

Gene therapy aims to replace a defective or a deficient protein at therapeutic or curative levels. Improved vector designs have enhanced safety, efficacy, and delivery, with potential for lasting treatment. However, innate and adaptive immune responses to the viral vector and transgene product remain obstacles to the establishment of therapeutic efficacy. It is widely accepted that endogenous regulatory T cells (Tregs) are critical for tolerance induction to the transgene product and in some cases the viral vector. There are two basic strategies to harness the suppressive ability of Tregs: in vivo induction of adaptive Tregs specific to the introduced gene product and concurrent administration of autologous, ex vivo expanded Tregs. The latter may be polyclonal or engineered to direct specificity to the therapeutic antigen. Recent clinical trials have advanced adoptive immunotherapy with Tregs for the treatment of autoimmune disease and in patients receiving cell transplants. Here, we highlight the potential benefit of combining gene therapy with Treg adoptive transfer to achieve a sustained transgene expression. Furthermore, techniques to engineer antigen-specific Treg cell populations, either through reprogramming conventional CD4⁺ T cells or transferring T cell receptors with known specificity into polyclonal Tregs, are promising in preclinical studies. Thus, based upon these observations and the successful use of chimeric (IgG-based) antigen receptors (CARs) in antigen-specific effector T cells, different types of CAR-Tregs could be added to the repertoire of inhibitory modalities to suppress immune responses to therapeutic cargos of gene therapy vectors. The diverse approaches to harness the ability of Tregs to suppress unwanted immune responses to gene therapy and their perspectives are reviewed in this article.

Keywords: adeno-associated virus vectors; adoptive transfer; cell therapy; chimeric antigen receptor regulatory T cells; gene therapy; lentiviral vectors; regulatory T cells; tolerance.

Figure 1

A scheme detailing combination regulatory T cell (Treg) adoptive therapy with gene transfer for tolerization of immune responses. FoxP3⁺ Treg cells with polyclonal specificity are harvested from the patient (1) and ex vivo expanded in the presence of high IL-2 concentrations and artificial APC (aAPC) or anti-CD3, anti-CD28 microbeads using GMP protocols (2); expanded Tregs are transplanted back into the patient (3), which is followed shortly by gene transfer (4).

Figure 2

Proposed mechanisms for immune suppression by adoptive transfer of polyclonal FoxP3⁺ regulatory T cell (Treg), chimeric antigen receptor (CAR)-Treg or TCR-transgenic (TCR-tg) Treg. (A) Adoptively transferred ex vivo expanded Treg with polyclonal specificity can interact with antigen-presenting cell (APC). Inhibitory receptors like CTLA-4 can compete with the costimulatory molecule CD28 to bind to CD80/86 receptors, and combined with other factors, it can lead to APC tolerization. Tolerogenic APCs interact with activated antigen-specific T effector (T_eff) cells, which leads to conversion of T_eff to induced Treg (iTreg). (B) Natural Treg engineered with TCR specificity for antigen (TCR-tg Treg) can recognize antigen presented by APCs, directly suppressing the APC’s capacity to costimulate T_eff cells. TCR-tg Treg can also directly inhibit CD4⁺ T helper cells, which in turn affects T cell help to antigen-specific B-cells. (C) Putative mechanisms for antigen recognition and suppression by CAR-Treg. CAR-Tregs may recognize either a B-cell bound antigenic epitope or antigen on the surface of APC, which can trigger the activation and proliferation of the CAR-Treg through transmembrane and intracellular-signaling domains. The mechanisms by which CAR-Tregs exert their suppressive effects are not clearly defined, but may include interactions with key cell types.