Regulatory T-cell therapy in Crohn's disease: challenges and advances

Abstract

The prevalence of IBD is rising in the Western world. Despite an increasing repertoire of therapeutic targets, a significant proportion of patients suffer chronic morbidity. Studies in mice and humans have highlighted the critical role of regulatory T cells in immune homeostasis, with defects in number and suppressive function of regulatory T cells seen in patients with Crohn's disease. We review the function of regulatory T cells and the pathways by which they exert immune tolerance in the intestinal mucosa. We explore the principles and challenges of manufacturing a cell therapy, and discuss clinical trial evidence to date for their safety and efficacy in human disease, with particular focus on the development of a regulatory T-cell therapy for Crohn's disease.

Keywords: Crohn's disease; T lymphocytes; immunology; immunoregulation; intestinal T cells.

Figure 1

Mechanisms of Treg-mediated suppression. Tregs use a multitude of mechanisms to promote a tolerogenic microenvironment and tissue repair. (A) Secretion of the anti-inflammatory cytokines, IL-10, TGF-β and IL-35, not only inhibit Teff proliferation but also suppress Th1 and Th17 effector function, both of which are key mediators of IBD. (B) Tregs express the high-affinity IL-2 receptor α-chain (CD25) consuming local IL-2 with greater affinity than effector cells. Teffs which are ‘starved’ of IL-2 exhibit restricted proliferation and undergo apoptosis. (C) Tregs coexpressing CD39 and CD73 disrupt metabolic processes in effector cells by converting ATP into pericellular adenosine, a potent inhibitor of Teff function. Additionally, adenosine stimulates TGF-β production, promoting development of pTregs. (D) Tregs are capable of secreting perforin, granzyme B and galectin-1 which are directly cytotoxic against Teffs. Activated Tregs also express TRAIL, inducing apoptosis of Teffs through the TRAIL/DR5 pathway. (E) Expression of CTLA-4 degrades DC-derived CD80 and CD86 leading to impaired CD28-mediated costimulation of T cells. DC function is further inhibited through the interaction of Treg-derived TIGIT and CD155 on DCs. This induces IL-10 production and suppresses IL-12. (F) In response to alarmins, Tregs produce AREG, an important regulator of tissue repair and regeneration. AREG, amphiregulin; CTLA-4, cytotoxic T lymphocyte associated protein 4; DC, dendritic cell; DR5, death receptor 5; IL, interleukin; pTregs, peripheral regulatory T cells; Teff, T effector lymphocyte; TGF-β, transforming growth factor beta; Th1, T helper 1 cell; Th17, T helper 17 cell; TIGIT, T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains; TRAIL, TNF-related apoptosis-inducing ligand; Treg, regulatory T cell. Figure generated using BioRender illustration software.