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Genetic Controls of Th17 Cell Differentiation and Plasticity

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Genetic Controls of Th17 Cell Differentiation and Plasticity EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 43, No. 1, 1-6, January 2011 Genetic controls of Th17 cell differentiation and plasticity Chen Dong1 Th cell differentiation is instructed by distinct environmental cytokines, which signals through Department of Immunology and Center for Inflammation and Cancer STAT or other inducible but generally ubiquitous MD Anderson Cancer Center transcription factors. These factors then upregulate Houston, TX, USA the expression of lineage-specific transcription fa- 1Correspondence: Tel, 1-713-563-3203; ctors, which function not only to promote its own Fax, 1-713-563-0604; E-mail, [email protected] lineage differentiation but also to inhibit the al- DOI 10.3858/emm.2011.43.1.007 ternate differentiation pathways. There are exten- sive cross-regulations of lineage-determining trans- cription factors. Moreover, there is growing evi- Accepted 22 December 2010 Available Online 23 December 2010 dence that Th cell lineage commitment can be plastic in certain circumstances. Here, I summarize Abbreviation: Th cells, T helper cells our current understanding on the genetic controls of Th17 cell lineage differentiation and discuss on the evidence and mechanisms underlying their Abstract plasticity. CD4+ T lymphocytes play a major role in regulation of adaptive immunity. Upon activation, naïve T cells dif- Transcriptional control of Th17 cell ferentiate into different functional subsets. In addition differentiation to the classical Th1 and Th2 cells, several novel effector T cell subsets have been recently identified, including Th17 cell differentiation can be induced by the Th17 cells. There has been rapid progress in character- combination of TGFβ and IL-6 or IL-21 (Dong, izing the development and function of Th17 cells. Here 2008). IL-1 also plays a crucial role in early Th17 cell differentiation (Chung et al., 2009). Several I summarize and discuss on the genetic controls of transcription factors have been shown as critical their differentiation and emerging evidence on their regulators of Th17 cell differentiation. plasticity. This information may benefit understanding and treating immune diseases. STAT3 Keywords: CD4-positive T-lymphocytes; cell differ- STAT3 has been reported to be a crucial com- entiation; cytokines; Th17 cells; transcription factors ponent of IL-6-mediated Th17-cell regulation. T cells deficient in SOCS3 (a negative regulatory of STAT3) were first found to have enhanced STAT3 After activation by antigen-presenting cells (APC), activity and IL-17 production in response to IL-23 naïve, antigen-specific CD4+ T cells differentiate (Chen et al., 2006). In the absence of STAT3 in T into effector T cells. Two decades ago, Coffman cells, defects were oberved not only in IL-17 and Mosman first discovered the heterogeneity of production, but also in the expression of IL-17F, effector T cells, which were then named as Th1 or IL-22 and IL-23R (Yang et al., 2007). Subse- Th2 cells (Mosmann and Coffman, 1989). Th1 and quently, STAT3 was also reported to be important Th2 cells are differentially induced and regulate for IL-21 expression and for IL-21-mediated Th17- immunity against intracellular and extracellular cell differentiation (Nurieva et al., 2007; Zhou et al., pathogens, respectively, as well as immunopa- 2007). Importantly, STAT3 deficiency greatly de- thologies such as autoimmunity and allergy. The creased the expression of RORγt and RORα, Th1/Th2 dichotomy has dominated the field of which are now known to be Th17-cell lineage- immune regulation until five years ago when IL- specific transcription factors (Yang et al., 2007; 17-expressing T cells were proposed to be a third Yang et al., 2008b). These results indicate an es- lineage of helper T cells (Harrington et al., 2005; sential function of STAT3 in the global regulation of Park et al., 2005). In addition to these so-called Th17-cell gene expression programs, possibly Th17 cells, additional T cell subsets were also through the induction of lineage-specific trans- discovered or studied, including T follicular helper cription factors. Consistently, in human hyper-IgE (Tfh) cells and IL-9-expressing “Th9” cells, etc. patients with STAT3 mutation, Th17 differentiation 2 Exp. Mol. Med. Vol. 43(1), 1-6, 2011 was found to be defective (Milner et al., 2008). to the retinoic acid-related orphan nuclear hor- mone receptor family that also includes RORβ (Jetten, 2004). An isoform of RORγ, RORγt is Smads exclusively expressed in cells of the immune TGFβ together with IL-6 drive Th17 cell differ- system (Eberl and Littman, 2003). Recently, Ivanov entiation. However, how TGFβ signals in this et al. identified RORγt as a candidate master process was not understood for some time. TGFβ regulator that drives Th17-cell lineage differ- signaling through a heteromeric TGFβRII and entiation (Ivanov et al., 2006). RORγt expression is TGFβRI complex, activates the phosphorylation of induced by TGFβ or IL-6, and overexpression of Smad2 and Smad3, which associate with the RORγt promoted Th17-cell differentiation when common partner Smad4, and translocates to the both Th1- and Th2-cell differentiation were block- nucleus (Feng and Derynck, 2005). Yang et al. ed. Conversely, RORγt-deficient T cells were de- showed that inhibition of TGFβ signaling in T cells fective in Th17-cell differentiation, especially in suppressed Th17 cell differentiation (Yang et al., terms of IL-17 and IL-17F expression, in response 2008a). However, Smad4 was not required for to TGFβ and IL-6 or IL-21 (Ivanov et al., 2006; Th17 cell differentiation in this study. Furthermore, Nurieva et al., 2007; Zhou et al., 2007). Martinez et al reported that in T cells deficient in In spite of these findings, residual Th17 cells are Smad3, Th17 cell differentiation was enhanced in still present in the absence of RORγt and mice vitro and in vivo (Martinez et al., 2009). Sub- lacking T-cell expression of RORγt can still develop sequently, Smad2 was reported by several groups EAE disease, which indicates that other factors are to positively regulate Th17 cell differentiation (Mal- also involved. Recently, Yang et al. reported that hotra et al., 2010; Martinez et al., 2010; Takimoto RORα is also expressed by Th17 cells; RORα et al., 2010). T cells deficient in Smad2 had expression was induced by TGFβ and IL-6 in a substantial reduced Th17 differentiation in vitro. STAT3-dependent manner (Yang et al., 2008b). Also Malhotra et al. and Martinez et al. reported Similar to RORγt, RORα overexpression pro- that Smad2 is required for Th17 response in vivo in moted Th17-cell differentiation when Th1- and host defense to pathogen infection and in auto- Th2-cell differentiation was inhibited, which could immune disease (Malhotra et al., 2010; Martinez et occur independent of RORγ. However, RORα al., 2010). Takimoto et al. analyzed T cells deficient deficiency in T cells only resulted in a selective in both Smad2 and Smad3 and found that they decrease in IL-17 and IL-23R expression and had even had a greater defect in Th17 cell differ- a very moderate inhibitory effect on EAE (Yang et entiation than Smad2-/- T cells (Takimoto et al., al., 2008b). Yang et al. further showed that over- 2010). Smad3 likely plays a redundant role in the expression of RORα and RORγt had a synergistic absence of Smad2. effect in promoting Th17-cell differentiation, espe- How Smad2 regulates Th17 cell differentiation is cially when T cells were cultured under polarized not understood. In the absence of Smad2 or both differentiation conditions for Th1 cells or Treg cells Smad2 and 3, there was no defect in upregulation (Yang et al., 2008b). In addition, compound mu- of Th17-specific transcription factors (Martinez et tations in both factors completely inhibited Th17- al., 2010; Takimoto et al., 2010). Martinez et al cell differentiation in vitro and in vivo and entirely showed that Smad2 enhanced Th17 cell differ- suppressed the development of EAE (Yang et al., entiation driven by RORγt (Martinez et al., 2010). It 2008b). Thus, RORα and RORγt have similar and is thus possible that Smad2 is not required for redundant functions. early Th17 cell differentiation but may serve as a co-factor for RORγt to mediate the expression of Th17-specific genes. The direct targets of Smad2 IRF4 need to be determined by genome-wide appro- In addition to the ROR factors, interferon-regu- aches. latory factor 4 (IRF4) was recently shown to be essential for Th17-cell differentiation (Brustle et al., 2007). IRF4 deficiency completely inhibited Th17- RORγt/RORα cell differentiation and protected mice against EAE. Th-cell lineage commitment is mediated by line- RORγt expression was markedly decreased in age-specific transcription factors. Similar to T-bet in Irf4-/- T cells following treatment with TGFβ and Th1 cells and GATA3 in Th2 cells, two retinoic IL-6, which suggests that IRF4 might be upstream acid-related orphan receptor were recently dis- of RORγt (Brustle et al., 2007). However, RORγt covered to regulate Th17-cell differentiation. RORγ, overexpression in Irf4-/- T cells only partially re- encoded by the Rorc gene, and RORα both belong stored Th17-cell differentiation. Therefore, the pre- Th17 cell differentiation and plasticity 3 cise function of IRF4 remains to be determined. required for Th17 cell development (Okamoto et al., 2010). The overexpression of IκBζ is not sufficient in driving Th17 cell differentiation but Ahr synergizes with RORγt or RORα. IκBζ may act by The aryl hydrocarbon receptor (AHR) is a type I binding directly to the regulatory region of the IL-17 nuclear receptor that has been recently reported gene. In vivo, Nfkbiz-/- mice have a defect in Th17 by two groups that AHR plays a crucial role in development and are resistant to EAE. Th17 differentiation. Both regulatory T cells and Th17 cells express AHR (Quintana et al., 2008; Veldhoen et al., 2008), although the expression of Epigenetic control of IL-17/IL-17F this receptor is significantly higher in Th17 cells expression compared to Tregs or any other Th subset (Veldhoen et al., 2008).
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