Regulatory T cells: exploring mechanisms for future therapies

In this two-part Review Series for Clinical & Experimental Immunology, we have invited experts in their fields to contribute review articles on the recent progress in understanding the genetic basis of regulatory T cell functional development, their role in ensuring tolerance in health, the underlying mechanisms underlying their dysfunction in diseased states and their use in cellular therapies for the treatment of a host inflammatory conditions in humans. The immune system requires a homeostatic equilibrium between the mechanisms that ensure self-tolerance, those that control the capacity to mount lifelong immunity to pathogenic microbes and those that attenuate effector mechanisms from inducing immune pathology. A large body of literature shows that CD4+ regulatory T (Treg) cells are a dominant mechanism regulating the decision fate of these different immunological outcomes. In the mid-1990s, research from the Sakaguchi laboratory showed that a subset of CD4+ T cells constitutively expressing the interleukin (IL)-2 receptor(R) alpha (α) chain (CD25), and subsequently the forkhead box protein 3 (FoxP3) transcription factor, in the resting immune system of normal rodents possess potent immunosuppressive functions in vitro and in vivo [1]. Since their first discovery nearly 25 years ago, significant efforts have been made to unravel the differences in developmental processes between Treg cells and conventional T cells which ultimately determines the fate of the global T cell population and outcome of immune responses [2,3]. Although sustained FoxP3 expression and activity is crucial for Treg cell differentiation and effector functions, it is now clear that other genetic variables, some upstream of FoxP3, also contribute to the genesis of this T cell subset [4]. Recent advances in Treg cell research have tackled some of the major conceptual questions pertaining to Treg cell development and function, and have unravelled comprehensive mechanisms underlying Treg cell generation. FoxP3 was defined as a master transcription factor driving the development of Treg cells. CD4+FoxP3+ Treg cells develop largely in the thymus (tTreg), but can be induced in the periphery (pTreg) throughout the course of immune responses. In 1950s, a spontaneous systemic auto-inflammatory phenotype was described in the scurfy mouse. Subsequently, the Sakaguchi, Ramsdell and Rudensky laboratories reported that the scurfy mutation in male mice resided within the foxp3 gene, and that this phenotype was a consequence of a FoxP3 deficiency. In humans, an X-linked familial autoimmune syndrome of undefined origin was also linked to mutations in the foxp3 gene, called the immune dysregulation, polyendocrinopathy enteropathy (IPEX) [5]. Sequencing of the foxp3 gene in IPEX revealed functionally deleterious mutations throughout the entire gene itself, and with a strong predilection for mutations in sequences encoding the DNA-binding forkhead domain of the protein, positioning FoxP3 as essential for dominant self-tolerance. Studies in scurfy mice and IPEX have established the critical role of FoxP3 in the multi-organ syndromes, and demonstrated that FoxP3-expressing Treg cells had cell-intrinsic capacity to negatively regulate immune responses. Indeed, the critical role of Treg cells in the maintenance of self-tolerance and regulation of immune responses has been clearly established. In their absence, an exaggerated immune response ensued that led eventually to the development of autoimmune disease. Since the initial discoveries in scurfy mice and IPEX syndrome in humans, defective Treg cell development, homeostasis and/or function has been associated with a plethora of chronic inflammatory conditions and autoimmune and chronic inflammatory diseases. The cell-extrinsic and -intrinsic mechanisms that dictate FoxP3 expression and downstream transcriptional activity and Treg cell development are areas of intense research, and will be discussed in the article by Bending et al. in this issue [6]. Treg cells have emerged as a central control point in the regulation of autoimmune and inflammatory responses, and deficits in this control can compromise immunoregulation. Small numbers of Treg cells reside within lymphoid organs and peripheral tissues, but their contribution to immune tolerance is so significant that defects in Treg cell function cause catastrophic immune disorders. Physical elimination or functional abrogation of tTreg cells from the periphery of normal mice leads to the spontaneous development of various autoimmune diseases, all prevented by inoculation of normal Treg cells. Furthermore, depletion of tTreg cells provokes effective immunity to tumors in otherwise non-responding animals, enhances immune responses to bacterial, fungal, protozoal, nematodal and viral microbes, triggers allergic responses to innocuous environmental agents and breaks feto–maternal tolerance during pregnancy. Thus, FoxP3+ tTreg cells regulate autoimmune responses, but also suppress a variety of pathological inflammatory responses to a wide spectrum of non-self antigens. Research in Treg cell biology has evolved at an astonishing pace in the past two decades, and has established a credible framework for their application in clinical settings. Insights into the mechanisms underlying Treg cell development has led to the first therapeutic applications involving induction of Treg cell generation in vivo. However, how Treg cells enter functional fates that differ from conventional, effector T cells still remains unclear. Future studies of the processes underlying development of Treg cells should focus on comprehensive analyses of the entire T cell receptor (TCR) repertoire, intra- and intercellular mechanisms that determine Treg cell generation and fate, and that pinpoint discriminating features between thymic and peripheral Treg cell development. The articles by Mohr et al. [7] and Attias et al. [8] will discuss the relative contribution of Treg cells in the control of autoimmune and chronic inflammatory diseases, and how developmental, homeostatic or functional defects contribute to disease onset. Understanding the mechanisms underlying Treg cell development is essential for the design and application of Treg cell-based immunotherapies [9]. Treg cell immunotherapy would enable target organ-specific immunosuppression, at the same time procuring benefits over traditional systemic, drug-induced immunosuppression which may induce opportunistic infections and cancers, detrimental side effects for patients. Moreover, antigen- or organ-specific Treg cells could provide long-term tolerance towards target antigens, in turn minimizing the number and extent of treatments. Several clinical trials have been elaborated for immune cell therapies to many solid tumour types, and non-cancer diseases as well, especially autoimmune diseases. Notably, the development of novel Treg cell therapies to treat various autoimmune or inflammatory diseases such as graft-versus-host disease (GVHD) in solid organ transplantation, autoimmune diseases [rheumatoid arthritis (RA), type 1 diabetes (T1D)], allergies and inflammatory bowel disease (IBD) has spawned great excitement in clinic settings. In the article by Macdonald et al. [10], the authors provide a comprehensive overview of how to design and exploit Treg cell-based therapies. Currently, there are numerous clinical trials exploring the use of Treg cell transfer or strategies to boost endogenous Treg cells (https://clinicaltrials.gov) [11], and these cell therapies have resulted in improved prognoses and reduced side effects. Most of these trials have employed polyclonal Treg cells derived from donors, although such cells are not target-specific in their effects. Due to their skewed TCR repertoire and higher reactivity for self-peptide recognition, Treg cells are well-poised to home to, and expand within, target organs to mediate antigen-specific suppression in situ. Thus, to confer specificity to their cells, some trials have utilized donor alloantigen-reactive Treg cells expanding in the graft recipient. More recently, several methods have been developed to generate targeted Treg cells. The most recent attempt involves application of a chimeric antigen receptor (CAR) technique to target Treg cells to specific antigens or more broad allo-antigens. In recent years, effector T cells have been successfully engineered to express antigen-specific TCRs or specific CARs that recognize a variety of antigens and exploited for clinically beneficial cell therapy in settings of transplantation and cancer. CAR-T cells specific for tumour antigens have shown great promise for effective adoptive cell therapies in some cancer treatments. In 2017, the first two CAR-T cell therapies for the treatment of a number of CD19-expressing B cell lymphomas received formal approval from the US Food and Drug Administration (FDA). Several hurdles affect the therapeutic potential of Treg cells in disease. Novel strategies will need to be developed to overcome the limitations related to survival and cell persistence in vivo, stability of the Treg cell functional phenotype and selective engagement or repression of antigen-specific responses in defined disease settings. In this regard, a better understanding of the genetic factors [single nucleotide polymorphisms (SNPs) or epigenetic], mechanisms of transcriptional regulation (splice isoforms, miRNAs and transcription factor activity) and post-translational modifications (phosphorylation, acetylation or ubiquitination) influencing FoxP3 gene and protein expression or activity will be required to further modulate the function of endogenous, or adoptively transferred expanded Treg cells in therapy. In this first of the two-part Review Series of Clinical & Experimental Immunology, we have assembled review articles that address several of the above-described themes. Herein, we present a collection of review articles focused on the mechanistic definition of Treg cell development and function, their functional dynamics in various mouse models and human diseases and their engineering and use in cell therapy of human disorders.

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