REVIEW The role of regulatory T cells in nervous system pathologies Samuel S. Duffy | Brooke A. Keating | Chamini J. Perera | Gila Moalem-Taylor School of Medical Sciences, University of New South Wales UNSW, Sydney, Australia Correspondence Gila Moalem-Taylor, Neuropathic Pain Research Group, Translational Neuroscience Facility, School of Medical Sciences, Wallace Wurth Building, Level 3, Room 355B, University of New South Wales, UNSW Sydney, NSW, 2052, Australia. Email: gila@unsw.edu.au Funding information This work was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC) to Gila Moalem-Taylor (APP1045343). Regulatory T (Treg) cells are a special subpopulation of immunosuppressive T cells that are essen- tial for sustaining immune homeostasis. They maintain self-tolerance, inhibit autoimmunity, and act as critical negative regulators of inflammation in various pathological states including autoim- munity, injury, and degeneration of the nervous system. Treg cells are known to convey both beneficial and detrimental influences in certain disease contexts, and accumulating research sug- gests that their action may be altered in a range of peripheral and central nervous system pathologies. In this review, we discuss emerging evidence for the dichotomous role of Treg cells in various neurological pathologies including multiple sclerosis, Guillain-Barr e syndrome, neuropathic pain, traumatic central nervous system injury, stroke, and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. We are in the early stages of uncovering the role of Treg cells in these conditions, and a better understanding of the ways in which these cells operate in the nervous system will enable us to develop novel therapeu- tic interventions. KEYWORDS neuroimmunology, nervous system, neuroinflammation, T cells 1 | INTRODUCTION Regulatory T (Treg) cells are a special T cell subset that has potent immu- nosuppressive properties. Treg cells play a pivotal role in maintaining self-tolerance, inhibiting autoimmunity, and acting as an endogenous brake to ensure that immune and inflammatory responses occur in bene- ficial proportion to their stimulus. Treg cells are capable of suppressing the activation, proliferation, and effector functions of T cells, natural killer cells, B cells, and antigen-presenting cells in vitro and in vivo (Saka- guchi, Yamaguchi, Nomura, & Ono, 2008). They are typically defined by expression of the interleukin (IL)-2 receptor a chain (CD25) and the fork- head box protein 3 (FoxP3) transcription factor. Although FoxP3 may be expressed on subsets of macrophages (Devaud et al., 2014), B cells (Noh, Noh, Kim, Kim, & Choi, 2012) and transiently in activated nonsup- pressive human CD4 1 T cells (Gavin et al., 2006), it is still widely consid- ered to be the most specific marker of Treg cells and is a critical regulator of their development and function (Fontenot, Gavin, & Rudensky, 2003; Gavin et al., 2007; Hori, Nomura, & Sakaguchi, 2003). FoxP3 1 Treg cells may be broadly classified into two main populations: thymus-derived naturally occurring Treg cells, and peripherally generated inducible Treg cells (Mills, 2004). In addition, there are several other Treg subsets such as FoxP3 2 iTreg cells, which can be either CD4 1 IL-10– producing Tr1 cells (Groux et al., 1997), transforming growth factor (TGF)-b–producing Th3 cells (Carrier, Yuan, Kuchroo, & Weiner, 2007), or IL-35–producing iTr35 cells (Collison et al., 2010) and naturally occur- ring CD8 1 CD122 1 Treg cells (Rifa’i, Kawamoto, Nakashima, & Suzuki, 2004); these are generally not referred to in this review, unless specifi- cally stated. Treg cells are known to exert their immunosuppressive capacity through a variety of mechanisms including suppression by granzyme-dependent cytolysis of effector cells (Cao et al., 2007; Significance It is now clear that the innate and adaptive immune system play a critical role in the development and progression of many nervous system pathologies, and the immunosuppressive properties of Treg cells appear to hold a powerful influence on the inflammatory milieu in multiple disease contexts. Recent evidence suggests that the influence of Treg cells is disease dependent, with both beneficial and detrimental roles reported in multiple sclerosis, Guillain-Barr e syndrome, neuropathic pain, traumatic central nervous system injury, stroke, and neurodege- nerative diseases including amyotrophic lateral sclerosis, Alzhei- mer's disease, and Parkinson's disease. Treg cells thus present themselves as promising candidates for therapeutic manipulation in certain clinical settings. J Neuro Res. 2017;1–18. wileyonlinelibrary.com/journal/jnr V C 2017 Wiley Periodicals, Inc. | 1 Received: 9 February 2017 | Revised: 28 March 2017 | Accepted: 6 April 2017 DOI: 10.1002/jnr.24073