The role of regulatory T cells in nervous system pathologies

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Regulatory T (Treg) cells are a special T cell subset that has potent immunosuppressive 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 beneficial 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 (Sakaguchi, Yamaguchi, Nomura, & Ono, 2008). They are typically defined by expression of the interleukin (IL)‐2 receptor α chain (CD25) and the forkhead 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 nonsuppressive human CD4+ T cells (Gavin et al., 2006), it is still widely considered 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+ 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− iTreg cells, which can be either CD4+ IL‐10–producing Tr1 cells (Groux et al., 1997), transforming growth factor (TGF)‐β–producing Th3 cells (Carrier, Yuan, Kuchroo, & Weiner, 2007), or IL‐35–producing iTr35 cells (Collison et al., 2010) and naturally occurring CD8+CD122+ Treg cells (Rifa'i, Kawamoto, Nakashima, & Suzuki, 2004); these are generally not referred to in this review, unless specifically 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; Gondek, Lu, Quezada, Sakaguchi, & Noelle, 2005), modulation of dendritic cell function (Tadokoro et al., 2006), and the elaboration of anti‐inflammatory cytokines including IL‐10, IL‐35, and TGF‐β (Vignali, Collison, & Workman, 2008). Metabolic disruption relating to “consumption” of local IL‐2 necessary for effector T cell proliferation (Pandiyan, Zheng, Ishihara, Reed, & Lenardo, 2007), the transfer of cyclic AMP through gap junctions into effector T cells (Bopp et al., 2007), cytotoxic T lymphocyte antigen 4 (CTLA4)‐dependent downregulation of the costimulatory molecules CD80 and CD86 on antigen‐presenting cells (Onishi, Fehervari, Yamaguchi, & Sakaguchi, 2008; Wing et al., 2008), and extracellular release of adenosine through concordant expression of CD39 and CD73 are also possible means of Treg‐mediated immunosuppression (Deaglio et al., 2007).
Emerging evidence suggests that in many peripheral and central nervous system (CNS) pathologies, the innate and adaptive immune system possess a powerful influence on disease progression. Although the CNS was commonly considered an immune‐privileged site where immune responses are minimal, recent studies have revisited this view. Indeed, it is now accepted that the CNS undergoes constant immune surveillance (Louveau et al., 2015; Ransohoff & Engelhardt, 2012), and the immune response has been proven to possess a strong modulatory capacity in autoimmunity, injury, and degeneration of the nervous system. Treg cells have been shown to convey both beneficial and detrimental influences in certain disease contexts. Whilst Treg cells are essential in the maintenance of self‐tolerance and the inhibition of harmful immune responses (Kronenberg & Rudensky, 2005), they can also suppress protective effector T cell responses that may operate to limit neurodegeneration in CNS pathology (Moalem et al., 1999; Schwartz & Baruch, 2014; Walsh & Kipnis, 2011).
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