Generation and function of induced regulatory T cells

Abstract

CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells are essential to the balance between pro- and anti-inflammatory responses. There are two major subsets of Treg cells, "natural" Treg (nTreg) cells that develop in the thymus, and "induced" Treg (iTreg) cells that arise in the periphery from CD4(+) Foxp3(-) conventional T cells and can be generated in vitro. Previous work has established that both subsets are required for immunological tolerance. Additionally, in vitro-derived iTreg cells can reestablish tolerance in situations where Treg cells are decreased or defective. This review will focus on iTreg cells, drawing comparisons to nTreg cells when possible. We discuss the molecular mechanisms of iTreg cell induction, both in vivo and in vitro, review the Foxp3-dependent and -independent transcriptional landscape of iTreg cells, and examine the proposed suppressive mechanisms utilized by each Treg cell subset. We also compare the T cell receptor repertoire of the Treg cell subsets, discuss inflammatory conditions where iTreg cells are generated or have been used for treatment, and address the issue of iTreg cell stability.

Keywords: TCR repertoire; Treg cells; Treg function; Treg stability; gene expression profiling; immunotherapy.

Figure 1

Mechanisms of regulatory T cell-mediated suppression. Regulatory T (Treg) cells can utilize several different suppressive mechanisms falling into three broad categories: (1) cell–cell contact-mediated suppression, (2) the metabolic disruption of effector T (Teff) cells, and (3) the secretion of inhibitory cytokines. (1) Contact-mediated suppression dampens the immunostimulatory properties of dendritic cells (DC) and occurs via the engagement of Treg cell inhibitory receptors such as CTLA-4 and LAG-3 with CD80/86 and MHC molecules on the DC, respectively. Delivery of granzyme B (Gzm B) to Teff cells leads to apoptosis. (2) Metabolic disruption of effector T cells is mediated by Treg cell delivery of cAMP to effector T cells via gap junctions, the generation of adenosine by the Treg cell ectoenzymes CD39 and CD73 which acts on Teff cell adenosine receptors (A2AR), and by Treg cell consumption of IL-2 thereby depriving Teff cells of growth factors. (3) Treg cells secrete inhibitory cytokines such as IL-10, IL-35, and TGF-β1, which inhibit both T cells and DCs.