Human regulatory T cells in autoimmune diseases

Human regulatory T cells (Tregs) play a critical role in preventing autoimmunity, and their failure contributes to autoimmune diseases. In recent years, our understanding of human Tregs has been greatly enhanced by improvements in the definition and isolation of pure human Tregs, as well as by the discovery of phenotypically and functionally distinct human Treg subsets. This progress has also yielded a better understanding of the mechanisms of human Treg suppression and the role of human Tregs in autoimmune diseases. An unexpected discovery is that human Tregs have considerable plasticity that allows them to produce the pro-inflammatory cytokine IL-17 under certain conditions. These recent advances highlight the importance of studying the roles of both mouse and human Tregs in autoimmunity.

Introduction

Human regulatory T cells (Tregs) were first isolated from peripheral blood and characterized as CD4⁺CD25^high T cells by several groups in 2001 [1, 2, 3, 4, 5, 6]. We now know that these cells play a critical role in preventing autoimmune diseases by suppressing self-reactive T cells – which are present in all healthy individuals – through incompletely understood mechanisms that involve cell-contact and secretion of inhibitory cytokines [7]. Tregs’ impressive suppressive ability extends not only to other CD4⁺ T cells, but also to suppression of proliferation, activation, and cytokine production by CD8⁺ T cells, B cells, antigen-presenting cells (APCs), and natural killer cells [8]. The transcription factor forkhead box P3 (FoxP3) is the canonical, specific marker for human Tregs and is thought to serve as the ‘master regulator’ in charge of Treg development and function [8, 9, 10]. In fact, mutations in FoxP3 lead to an absence of Tregs, which in turn results in the severe, multi-organ autoimmunity syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) [11]. It should be noted that other types of suppressive regulatory T cells have been described, including peripherally induced Tregs, Tr1, Th3, natural killer T cells, and certain CD8⁺ cells. These cells gain their suppressive abilities in the periphery, in response to certain cytokines or stimulation conditions. By contrast, human FoxP3⁺ natural Tregs develop their specialized suppressive abilities centrally in the thymus [12]. These human natural Tregs will be the focus of this review.

In addition to rare Mendelian genetic diseases such as IPEX, it has become increasingly clear that Tregs are of tremendous importance to the pathogenesis of common human diseases. Defects in the in vitro suppressive function of Tregs occur in patients with numerous autoimmune diseases, including relapsing-remitting multiple sclerosis (RRMS), type 1 diabetes (T1D), psoriasis, myasthenia gravis, and rheumatoid arthritis (RA) [7]. Moreover, Tregs play increasingly recognized roles in a wide variety of human diseases that involve inflammation, notably cancers and infectious diseases [13, 14]. In addition, infusion and pharmacological modulation of Tregs have been proposed as immune therapies for autoimmune diseases, cancer, infectious diseases, and for achieving tolerance to transplanted organs [8].

Although Tregs are studied most extensively in mice, Tregs of mice and humans exhibit many fundamental differences. First, there are differences in FoxP3 expression, including alternatively spliced FoxP3 isoforms with distinct functions present in humans but not mice and the expression of low levels of FoxP3 in CD4⁺CD25⁻ cells following T-cell receptor (TCR) activation in humans but not mice [9, 10, 15, 16•, 17, 18]. Second, mouse models of autoimmune diseases are well known to differ from their human counterparts. Third, whereas mouse Treg isolation typically utilizes FoxP3-GFP reporter mice to take advantage of the specificity of FoxP3 as a Treg marker, human Treg isolation from blood must rely on cell-surface characteristics of Tregs. Fourth, human Tregs exhibit greater heterogeneity of phenotype and suppressive function than mouse Tregs, such that human Tregs are now generally divided into phenotypically and functionally distinct subsets for experimentation [19••, 20••, 21]. These key differences dictate that future Treg and autoimmune disease research must be conducted in human systems as well as in mouse models.

In this review, we focus on recent advances in our understanding of how to define and isolate homogenous FoxP3⁺ human Tregs, phenotypically and functionally distinct Treg subsets, Treg plasticity, mechanisms of Treg suppression, the role of human Tregs in autoimmune diseases, and conclude with remarks about several promising avenues for future human Treg research.