STAT Transcription Factors in T Cell Control of Health and Disease

CHAPTER FOUR

STAT Transcription Factors in T Cell Control of Health and Disease☆ R. Goswami*,1,2, M.H. Kaplan†,1 *Institute of Life Sciences, Ahmedabad University, Ahmedabad, India † Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, United States 2 Corresponding author: e-mail address: [email protected]

Contents 1. Engagement of the Jak-STAT Signaling Pathway 2. Jak-STAT Molecules in T Helper Cell Differentiation 2.1 Th1 Cells 2.2 Th2 Cells 2.3 Th17 Cells 2.4 Treg Cells 2.5 Tfh Cells 2.6 Th9 Cells 3. STAT Molecules in the Development of Cytotoxic T Cells 3.1 Tc1 Cells 3.2 Tc2 Cells 3.3 Tc17 Cells 3.4 Tc9 Cells 4. STATs Mutations Result in Patient Immunodeficiency 5. STAT Molecules in Allergic Inflammation 5.1 Jak Proteins in Allergic Inflammation 5.2 STAT1 5.3 STAT3 5.4 STAT4 5.5 STAT5 5.6 STAT6 6. Role of STAT Molecules in Intestinal Inflammation 6.1 STAT1 6.2 STAT3 6.3 STAT4

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Author contributions: Goswami R. and Kaplan M.H. wrote the paper.

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Conflict of interest statement: Authors declare no conflict of interest for this chapter.

International Review of Cell and Molecular Biology, Volume 331 ISSN 1937-6448 http://dx.doi.org/10.1016/bs.ircmb.2016.09.012

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2017 Elsevier Inc. All rights reserved.

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6.4 STAT5 6.5 STAT6 7. Jak-STAT Molecules in Autoimmune Diseases 7.1 STAT1 7.2 STAT3 7.3 STAT4 7.4 STAT5 7.5 STAT6 8. Blocking Cytokine Signaling to Treat Disease 8.1 STAT1 Inhibitor 8.2 STAT3 Inhibitor 8.3 STAT4 Inhibitor 8.4 STAT5 Inhibitor 8.5 STAT6 Inhibitor 9. Conclusion References

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Abstract The Jak-STAT pathway is one of many pleiotropic signaling pathways that plays an important role in organismal development and in response to changing environmental cues. As a key signaling cascade for cytokines and growth factors, Jak-STAT plays central role in the innate and adaptive immune system. Cytokines control the stability, commitment, and maturation of cytotoxic and helper T cells, parts of the adaptive immune system that mediate immunity to pathogens and are linked to inflammatory diseases. Dysregulation of Jak-STAT protein expression or function leads to autoimmunity, allergic diseases, and cancer. Because of their central role in these responses, Jak and STAT molecules have been targeted to develop therapeutics. This review extensively discusses the mechanism of how Jak-STAT signaling in T cells defines our immune responses in the battle against foreign pathogens.

1. ENGAGEMENT OF THE JAK-STAT SIGNALING PATHWAY Innate immune system activation and education after pathogen recognition in concert with secretion of cytokines and chemokines lead to adaptive immune cell activation (Medzhitov, 2007). Adaptive immune responses begin when an antigen is presented by an antigen presenting cell in the context of class II MHC to a specific T cell receptor. Following this interaction, an activated naı¨ve T cell can give rise to distinct T helper (Th) subsets that develop in response to varying stimuli including the cytokine environment (Zhu et al., 2010). Cell fate determination in each lineage requires at least two types of transcription factors: the lineage-associated factors, and the

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signal transducers and activators of transcription (STAT) proteins that are activated by extracellular cytokines (Levy and Darnell, 2002). The mammalian STAT family ranges in size from 750 to 850 amino acids and 80–100 kDa in molecular mass and has seven members in the family including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6 (Schindler et al., 2007). The function of STATs includes signal transduction and gene regulation. The STAT protein domain structure includes an N-terminal domain, a coiled coil, and a DNA-binding domain (Levy and Darnell, 2002). STAT molecules also include an SH2 domain (a phosphotyrosine-binding domain required for receptor recognition and dimerization), the canonical tyrosine that is phosphorylated by Jak proteins, and a C-terminal transcriptional activation domain (Levy and Darnell, 2002) (Fig. 1A).

A

Jak kinase structure NH2 STAT domain structure NH2

FERM

SH2-like

Coiled-coil

Kinase

COOH

Transactivation

COOH

Pseudokinase SH2

DNA binding

Cytokine

B Cytokine receptor

STAT

JAK

JAK

JAK

JAK

JAK

JAK

STAT

ty ivi

tion

t

k

k oc

Bl

ac

Ja

ck

Blo

tor

ep -rec

T STA

Block

ocia

STAT

ass

ization

STAT

mer TAT di

S

Inhibitors Block

STAT

DNA bi

nding

STAT

STAT

Fig. 1 Jak-STAT signaling. (A) The domain structure of Jak and STAT has been shown. (B) After a cytokine binds to its receptor, Jak molecules are activated and phosphorylate each other. In addition, Jaks phosphorylate the receptors, creating a docking site for STAT proteins. JAKs then phosphorylate STAT proteins, allowing them to either homoor heterodimerize based on reciprocal phosphotyrosine and SH2 domain interactions. STAT dimers then translocate to the nucleus where they bind to a consensus TTC(N3) GAA-binding site and activate transcription. Points of potential therapeutic inhibition of the pathway are indicated.

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Activation of STAT molecules requires the activity of cytoplasmic kinases called Jaks (Janus kinases) (Aaronson and Horvath, 2002). Jak1, Jak2, Jak3, and Tyk2 (tyrosine kinase 2) constitute the mammalian Jak family of proteins (Yamaoka et al., 2004). Jaks are larger than STAT proteins with more than 1100 amino acids and molecular masses of 120–140kDa (Yamaoka et al., 2004). Jaks have an N-terminal FERM domain that is required for binding to cytokine receptors (Yamaoka et al., 2004). In addition, Jaks have an SH2 domain, a pseudokinase domain, and a C-terminal kinase domain (Yamaoka et al., 2004) (Fig. 1A). The pseudokinase domain has a key regulatory function despite not having catalytic activity, while the FERM domain controls catalytic activity by binding to the kinase domain (Yamaoka et al., 2004). Cytokines and growth factors upon binding their cognate receptors induce receptor dimerization or oligomerization leading to transphosphorylation and activation of Jaks that phosphorylate docking sites for the SH2 domain of STAT molecules (Levy and Darnell, 2002). Once STATs are recruited, they become phosphorylated at specific tyrosine residues near the C-terminal end. Via reciprocal phosphotyrosine–SH2 interactions, parallel STAT homo- or heterodimers are formed (Wenta et al., 2008). Importin family protein members associate with activated STATs and transport them to the nucleus where they regulate the expression of genes that contain cognate GAS (gamma-interferon activation site) promoters in their sequences (Meyer and Vinkemeier, 2004). Along with the Jak and STAT proteins, induction of a gene requires the cooperation of transcription factors and transcriptional coactivators and repressors (Paulson et al., 1999). Some of the ability of STATs to transactivate gene expression is linked to serine phosphorylation in the STAT protein transactivation domain (Darnell, 1997). STATs are dephosphorylated upon the completion of transcription by nuclear protein tyrosine phosphatase (Mertens and Darnell, 2007). Additional domains also impact STAT function. The STAT protein N-domain plays a role in dimerization, tetramerization, and protein–protein interaction (Vinkemeier et al., 1998). The STAT DNA-binding domain forms an immunoglobulin-like structure and is involved in nuclear translocation (Ma and Cao, 2006). Once in the nucleus, STAT homo- and heterodimers bind DNA at GAS homology sequences that have a consensus sequence of TTCN2–4GAA (Lim and Cao, 2006) and activate transcription (Zhang et al., 1997). Apart from the GAS element, the ISRE is bound by the type 1 IFN-activated multimeric ISGF3 complex (containing STAT1, STAT2, and IRF9) and has the consensus sequence AGTTN3TTTC

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(Ma and Cao, 2006). Unphosphorylated STAT molecules can also act as transcriptional coactivators similar to, but with less activity than their phosphorylated counterparts (Braunstein et al., 2003). In the absence of cytokine receptors, Jaks are located in cytosol; however, when associated with the receptors, Jaks move to plasma membrane and endosomes (Hofmann et al., 2004). In the four-member family of Jaks, Jak3 is the only member not ubiquitously expressed, with expression restricted to hematopoietic lineage cells (Yamaoka et al., 2004; Musso et al., 1995). The requirement for individual Jak proteins is determined by usage of the cytokine/growth factor receptor complex. Both Jak1 and Jak3 are required for signaling by cytokines that use common γ chain (γc) receptor subunit (Ghoreschi et al., 2009). Jak1 and Jak2 are required for cytokine signaling that share the subunit gp130 (Lupardus et al., 2011; Sriram et al., 2004). Growth hormones, erythropoietin, thrombopoietin signal via Jak2 (Brooks et al., 2014; Drachman et al., 1999; Witthuhn et al., 1993). Tyk2 is required for IL-12-mediated signaling but plays limited role in interferon signaling (Shimoda et al., 2000). The Jak-STAT signaling pathway is shown in Fig. 1B, and the activation of JAKs and STATs with specific receptors is summarized in Tables 1 and 2.

Table 1 List of Cytokines-Activating STAT Molecules in T Cells STAT Activating Molecules Cytokines Required for Th Subset (References)

STAT1

IFN-γ, IFN-α/β, Th1 (Afkarian et al., 2002), Th9 (Vegran et al., IL-27 2014)

STAT3

IL-6, IL-21, IL-23, IL-27

Th2 (Stritesky et al., 2011), Th17 (Mathur et al., 2007; Nurieva et al., 2007; Yang et al., 2007), Tfh (Nurieva et al., 2008; Wu et al., 2016a,b)

STAT4

IL-12, IL-23

Th1 (Kaplan et al., 1996b; Nishikomori et al., 2002; Thierfelder et al., 1996), Th17 (Glosson-Byers et al., 2014; Mathur et al., 2007)

STAT5

IL-2, IL-9, IL-15, TSLP

Th1 (Cooley et al., 2015), Th2 (Zhu et al., 2003), Th9 (Bassil et al., 2014; Gomez-Rodriguez et al., 2016; Liao et al., 2014), Treg (Burchill et al., 2007; Davidson et al., 2007; Furtado et al., 2002)

STAT6

IL-4, IL-13

Th2 (Kagami et al., 2001; Kaplan et al., 1996a; Shimoda et al., 1996; Takeda et al., 1996), Th9 (Goswami et al., 2012)

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Table 2 List of Cytokines/Receptors-Activating Jak Molecules Jak Molecules Activating Cytokines Associated Cytokine Receptors

Jak1

IFN-α/β, IFN-γ, IL-2, IL-4, IL-6, IL-7, IL-9, IL-15, IL-21

IL-6R, IFN-γR1, IFNAR2, IL-7Rα, IL-9Rα, IL-15Rα, IL-21Rα

Jak2

IFN-γ, IL-3, IL-5, IL-12

IFN-γR2, IL-3Rα, IL-5Rα, IL-12Rβ2, IL-23R

Jak3

IL-2, IL-4, IL-7, IL-9, IL-15, IL-21

Common γ chain

Tyk2

IFN-α/β, IL-6, IL-12, IL-23

IFNAR1, IL-12Rβ1, IL-23R, gp130

2. Jak-STAT MOLECULES IN T HELPER CELL DIFFERENTIATION Each T helper cell lineage is dependent on distinct Jak-STAT molecules for its differentiation and effector functions. Activation is dependent on the cytokine environment in which the cell develops. In this section we are going to highlight our current understanding of the roles played by JakSTAT molecules in each T helper cell differentiation.

2.1 Th1 Cells Th1 cells are characterized by the production of IFN-γ and lymphotoxin-α (Romagnani, 2000). Naı¨ve CD4 + T cells polarize into Th1 cells when cultured in the presence of IL-12 (Hsieh et al., 1993). Th1 cells are critical for immunity against intracellular bacteria, fungi, protozoa (Fieschi et al., 2003; Hsieh et al., 1993), and IFN-γ specifically can activate and enhance microbicidal activity of macrophages (Suzuki et al., 1988). Lymphotoxin-α maintains host defense and inflammation and the development of Peyer’s patches (Fu and Chaplin, 1999; Ware, 2005). Th1 cells require IL-12 and IFN-γ for their differentiation (Trinchieri et al., 2003). IL-12 signals through activated Jak2 and Tyk2, and activates STAT4, the key transcription factor for Th1 commitment (Zhu and Paul, 2010). In the absence of the STAT4 signal, Th1 cell development is severely impaired when stimulated by either IL-12 or Listeria monocytogenes, and the cells have a propensity for differentiating into Th2 cells (Kaplan et al., 1996b;

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Thierfelder et al., 1996). Deletion of the STAT4 gene leads to disrupted IL-12 functions such as inhibition of IFN-γ. The master regulator of Th1 cells, T-bet requires the help of STAT4 to complete Th1 cell differentiation (Thieu et al., 2008). One study however reported that activated STAT4 can induce Th1 cell differentiation independent of IL-12Rβ2 chain expression and signaling (Nishikomori et al., 2002). STAT4-dependent Th1 polarization is amplified by IL-12 synergy with IL-18 (Barbulescu et al., 1998; Ouyang et al., 1999; Yang et al., 1999). During viral infection T-bet and STAT4 activates ST2, receptor of the alarmin IL-33 to induce antiviral Th1 response (Baumann et al., 2015). Importantly, the IFN-γ signal is also required for Th1 development. STAT1-deficient mice have attenuated Th1 differentiation, and IFN-γ signaling is mediated by STAT1 (Afkarian et al., 2002). In the absence of STAT3, there is increased propensity of CD4 + T cells to induce the expression of T-bet (Yang et al., 2007). STAT3-deficient naı¨ve CD4+ T cells demonstrate impaired germinal center formation, but enhanced expression of IFN-induced genes akin to a Th1 cell phenotype that can be attenuated by blocking IFN-αβ receptor (Ray et al., 2014). When developing T helper cells are treated with the pleiotropic cytokine IL-21, the IL-12/STAT4 signaling is diminished; thereby attenuating Th1 cell differentiation (Wurster et al., 2002). IL-21 inhibits IFN-γ production by developing Th1 cells in mice via eomesodermin repression (Suto et al., 2006). However, this repression was not dependent on STAT1 and STAT4 molecules (Suto et al., 2006). Similarly in human cells, IL-21 inhibited Th1 cell differentiation by downregulating T-bet expression (Kastirr et al., 2014). Changes in the cytokine microenvironment result in varied plasticity among T helper cell populations. IL-15 signaling via trans-presentation results in activation of STAT5 in maintaining Th1 cell differentiation, otherwise important in Th2 cell differentiation (Cooley et al., 2015). Contrary to this observation, Tosiek et al. (2016) observed that the absence of IL-15 does not alter Th1 cell development. Therefore, multiple Jak and STAT molecules coordinate the development of Th1 cells that depend on the molecules present in the microenvironment.

2.2 Th2 Cells Naı¨ve T cells differentiate into Th2 cells by antigen in the presence of IL-4 (Paul and Zhu, 2010). These cells produce IL-4, IL-5, and IL-13, which are critical for providing defense against extracellular parasites such as helminths

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(Zhu and Paul, 2008). IL-4 mediates IgE class switching in B cells and acts as a positive feedback loop in Th2 differentiation (Kopf et al., 1993; Le Gros et al., 1990; Swain et al., 1990). IL-5 functions as eosinophil development and recruitment cytokine, while IL-13 plays an important role in reducing worm burden and inducing airway inflammation and hypersensitivity (Coffman et al., 1989; Urban et al., 1998; Wynn, 2003). IL-4 signals via STAT6, which is required for Th2 development in vitro (Kaplan et al., 1996a; Shimoda et al., 1996; Takeda et al., 1996). Mice injected with neutralizing IL-4 antibodies or Stat6
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mice have defective worm clearance after nematode infection. In STAT6VT mice (where STAT6 is constitutively activated), CD4 + T cells have a propensity toward Th2 cell lineage (Bruns et al., 2003; Else et al., 1994; Sehra et al., 2008; Takeda et al., 1996). However, in the absence of STAT6 the development of some Th2-cytokine secreting cells can occur in vivo (Jankovic et al., 2000; van Panhuys et al., 2008). IL-4R/STAT6 signaling is responsible for generating memory IL-4 responses and stabilization of Th2 phenotype (Finkelman et al., 2000; Jankovic et al., 2000). The expression of lineage-specific transcription factors of Th2 cells, Gfi-1, and Gata3 also depend on STAT6 (Lee and Rao, 2004; Zhu et al., 2002). IL-4/ STAT6-induced genes were downregulated in tissues during parasite infection in IL-21R-deficient mice, suggesting that IL-21 receptor signaling enhances effector Th2 function (Pesce et al., 2006). Apart from the IL-4/STAT6 pathway, IL-2-mediated STAT5 activation induces the production of IL-4, IL-5, and IL-13 by Th2 cells (Zhu et al., 2003). By upregulating IL-4Rα, IL-2/STAT5 primes IL-4 production by Th2 cells (Cote-Sierra et al., 2004; Liao et al., 2008). Even though IL-4/STAT6 signal is intact in Stat5A-deficient mice, Th2 cell development is impaired, possibly from the reduced IL-4R expression (Kagami et al., 2001). Overexpression of either Stat5A or Stat5B can rescue Th2 differentiation in Stat5A
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mice (Kagami et al., 2001). In the absence of STAT6, constitutively active Stat5A expression can induce restricted Th2 cytokine production and allergy airway inflammation (Takatori et al., 2005; Zhu et al., 2003). STAT3, required for differentiation and effector function of Th17 and Tfh cells, is also activated in Th2 cells (Nurieva et al., 2008; Stritesky et al., 2011; Yang et al., 2007). In the absence of STAT3 there is impaired Th2 cytokine production and attenuated Th2-specific transcription factor expression (Lim et al., 2015; Stritesky et al., 2011). STAT3 cooperates with STAT6 to promote Th2 cell development (Stritesky et al., 2011). STAT3 also cooperates with the STAT6 signal in providing B cell help

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(Mari et al., 2013). Thus, activation of multiple Jak-STAT pathways is pivotal in the development of Th2 cells.

2.3 Th17 Cells Th17 cells are proinflammatory cells that secrete IL-17A, IL-17F, IL-21, and IL-22 and provide immunity to several extracellular pathogens including defense against infections from Candida, Citrobacter, and Klebsiella (Happel et al., 2005; Huang et al., 2004; Mangan et al., 2006). The differentiation of Th17 cells requires TGF-β, IL-6, and IL-21 (Bettelli et al., 2006; Korn et al., 2007; Mangan et al., 2006; Veldhoen et al., 2006a). However, an alternative mode of pathogenic Th17 cells differentiation occurs without TGF-β signaling (Ghoreschi et al., 2010). IL-23, though not required for the development of Th17 cells, is required for Th17 cell maintenance (McGeachy et al., 2007; Stritesky et al., 2008). The cytokine IL-1β increases IL-23 responsiveness and promotes Th17 differentiation (Cua et al., 2003; Veldhoen et al., 2006b). Th17 polarizing cytokines IL-6, IL-21, and IL-23 activate STAT3 (Nurieva et al., 2007; Yang et al., 2007; Zhou et al., 2007). That STAT3 plays an important role in Th17 cell development has been shown in several studies (Mathur et al., 2007; Yang et al., 2007). In the absence of STAT3, CD4 + T cells have impaired IL-17A, IL-17F, IL-22, and IL-23R expression (Yang et al., 2007). Stat3
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T cells exhibit reduced expression of RORγt and RORα, the Th17 cell lineage-specific transcription factors (Yang et al., 2007, 2008). Expression of Foxp3, the transcription factor which is required for Treg differentiation, is attenuated by IL-6/STAT3 signal. The cytokine IL-23 signals through both STAT3 and STAT4 in Th17 cells. IL-17 production from Th17 cells stimulated with IL-23 and IL-18 requires STAT4 (Mathur et al., 2007), though STAT4 might also contribute to IL-23R expression in a subset of T cell populations (Glosson-Byers et al., 2014). IFN-γ, IL-27, and other STAT1-activating cytokines can repress Th17 cell development via T-bet-dependent and STAT1-dependent mechanisms (Villarino et al., 2010). IL-27 enhances Th17 differentiation in the absence of STAT1 activation, and the ratio of activated STAT3 to activated STAT1 is critical for this differentiation (Peters et al., 2015). Th17 cells, which lose the ability to express IL-17 and secrete IFN-γ owing to plasticity, do not depend on STAT1 and STAT4 (Duhen et al., 2013). However, another report has suggested that the late transition of from IL-17 to IFN-γ requires both T-bet and STAT4 (Lee et al., 2009).

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IL-15 regulates the differentiation of Th17 cells via STAT5 (Pandiyan et al., 2012). IL-17 induces STAT5 binding to Il17 gene in Th17 cells and downregulates IL-17 production independent of RORγt, IFN-γ, and Foxp3 (Pandiyan et al., 2012). Similarly, naı¨ve CD4+ T cells from Il15 and Il15rdeficient animals demonstrate increased production of IL-17 (Pandiyan et al., 2012). In the absence of STAT6, Th17-specific transcription factors are upregulated during glomerulonephritis (Summers et al., 2011). Thus, Jak-STAT signaling orchestrates Th17 cell development.

2.4 Treg Cells Regulatory T cells belong to a distinct T cell subset that controls proinflammatory responses of effector Th cells (Sakaguchi et al., 1995). Tregs suppress T cell activation and protect elimination of commensal bacteria by the immune system (Baecher-Allan et al., 2002; Dembic, 2008). Thymically-derived Treg cells (tTregs) derived from thymus provide suppressive functions. Naı¨ve CD4 + T cells exposed to TGF-β gives rise to Tregs in the periphery (pTregs, or in vitro-derived iTregs), which have similar properties (DiPaolo et al., 2007). iTregs produce the suppressive cytokine TGF-β (Li et al., 2006). Various markers used to identify Tregs including CD25, cytotoxic T lymphocyte-associated antigen 4 (CTLA4), glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR), and CD127 (Liu et al., 2006; McHugh et al., 2002; McNeill et al., 2007; Read et al., 2000; Sakaguchi et al., 1995; Seddiki et al., 2006; Takahashi et al., 2000). IL-2/IL-2R plays a critical role in Treg cell development (Malek and Bayer, 2004). Though controversy remains on the actual role of IL-2/IL-2R signaling, it is suggested to be required for Treg activation, function, and survival but not for homeostasis (Burchill et al., 2007; Davidson et al., 2007; D’Cruz and Klein, 2005; Furtado et al., 2002). Several studies have reported that IL-2/STAT5 signaling is required for the development of Treg cells (Burchill et al., 2007; Davidson et al., 2007). In the absence of STAT5, Treg cell development is impaired, while reconstitution of IL2rb
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mice with activated STAT5 restores Treg development (Burchill et al., 2007). STAT5 binds directly to the Foxp3 gene, the master regulator of Treg cells (Burchill et al., 2007). Therefore, STAT5 could directly induce Foxp3 expression (Burchill et al., 2007; Yao et al., 2007). STAT3, though required for Th17 development impairs the Treg phenotype and in vivo Treg differentiation (Pallandre et al., 2007). STAT3 binds

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to a silencer in the Foxp3 gene, reduces Smad3 binding, and inhibits the expression of Foxp3 (Xu et al., 2010; Yao et al., 2007). The STAT3 pathway may be important for IL-21-mediated impairment of Treg cell homeostasis (Attridge et al., 2012; Battaglia et al., 2013). Other STAT molecules including STAT4 and STAT6 repress Treg development, potentially through a similar mechanism (Chapoval et al., 2010; O’Malley et al., 2009; Takaki et al., 2008; Xu et al., 2011). A function for STAT1 in the development of Treg has been reported by regulating T-bet expression in Treg cells (Yu et al., 2015). IFN-γ/STAT1 axis is responsible for the inhibitory effect on the development of iTregs (Chang et al., 2009). Overall, the coordinated action of the Jak-STAT signaling cascade is required to provide immunomodulation by Treg cells.

2.5 Tfh Cells Follicular T helper or Tfh cells are CD4 + T cells that are required to provide B cell help leading to antibody production, somatic hypermutation, and class switching to generate long-lasting humoral immunity (Crotty, 2011). Tfh cells were identified in human tonsils with CD4 + T cells expressing high levels of CXCR5 (Breitfeld et al., 2000; Kim et al., 2001; Schaerli et al., 2000). The cytokines IL-6 and IL-21 promote Tfh cell differentiation (Chtanova et al., 2004; Eddahri et al., 2009; Nurieva et al., 2008; Suto et al., 2008). IL-6 has been demonstrated to induce IL-21, which is also produced by Tfh cells (Eddahri et al., 2009; Nurieva et al., 2008; Suto et al., 2008). IL-21 signaling is required for increased CXCR5 expression on Tfh cells (Vogelzang et al., 2008). There may be some redundancy in some of these signals as one study suggests that the absence of one of these cytokines does not affect Tfh cell numbers, but combined deficiency of both IL-6 and IL-21 leads to significantly reduced Tfh cell numbers (Eto et al., 2011). Tfh cells are characterized by the expression and production of CXCR5, inducible costimulator (ICOS), programmed death-1 (PD-1), and IL-21 (Breitfeld et al., 2000; GoodJacobson et al., 2010). Mice with disrupted ICOS–ICOS ligand interaction or patients with ICOS mutations have decreased Tfh cell numbers (Akiba et al., 2005; Bauquet et al., 2009; Bossaller et al., 2006). Studies suggest that ICOS signaling via PI3K is important to increase expression of Tfh-specific genes such as c-Maf and IL-21 (Bauquet et al., 2009; Gigoux et al., 2009; Rolf et al., 2010). Studies in mice deficient in PD-1 or its ligand PD-L1 indicate that PD-1/PD-L1 interactions may

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control long-lived plasma cells either positively or negatively (Good-Jacobson et al., 2010; Hamel et al., 2010; Hams et al., 2011). Both IL-6 and IL-21 signal through STAT3 and STAT3-deficient CD4 + T cells demonstrate impaired differentiation of Tfh cells (Nurieva et al., 2008). Mice having T-cell-specific deletion of STAT3 demonstrate defective germinal center B cell formation (Nurieva et al., 2008). However, one report suggests normal CXCR5+ CD4+ T cells in Stat3CD4
/
mice (Eddahri et al., 2009), suggesting that the requirement for STAT3 in Tfh cells might depend on the local microenvironment. The expression of IL-4 and Bcl6 is impaired by STAT3 in Tfh cells (Wu et al., 2015a). Regulatory Tfh cells (Tfr cells), a specific subset of regulatory T cells that modulate Tfh cytokine production and germinal center reaction, depend on STAT3 (Wu et al., 2016a,b). Loss of STAT3 inhibits differentiation of Tfr cells and enhances antigen-specific IgG antibodies (Wu et al., 2016b). IL-12/STAT4 signaling induces genes that contribute to both Tfh and Th1 cell phenotypes during early Th1 differentiation (Nakayamada et al., 2011). STAT5 negatively regulates Tfh cell differentiation and function (Johnston et al., 2012; Nurieva et al., 2012). STAT5 inhibits the expression of CXCR5, c-Maf, and IL-21 in Tfh cells but positively regulates the expression of Blimp-1 (Nurieva et al., 2012). In the absence of STAT5, CD4 + T cells have increased germinal center B cell numbers and Tfh cell development (Johnston et al., 2012; Nurieva et al., 2012). Both STAT1 and STAT3 are required for early differentiation of Tfh cells during an acute viral infection (Choi et al., 2013). IFN-γ/IFN-γR signals via STAT1 to form germinal centers (Domeier et al., 2016). Type I interferons activate STAT1 which bind to Bcl6, the master regulator of Tfh cells, to induce the differentiation of Tfh cells (Nakayamada et al., 2014). The development of human Tfh cells requires TGF-β signaling and the activation of STAT4, features that are not observed in mouse Tfh cells (Schmitt et al., 2014). STAT4 promotes a transition stage of Tfh and Th1 cells whereby IFNγ and T-bet negatively regulate the development of Tfh cells (Nakayamada et al., 2011). Cooperation of STAT3 and STAT6 is required for IL-4 production by Tfh cells (Sahoo et al., 2015). By binding to many genes pivotal for Tfh cell differentiation, STAT molecules have emerged to be very important.

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2.6 Th9 Cells The newest member of CD4+ T cell family is the Th9 cell. Culturing Th2 cells with TGF-β or treating naı¨ve CD4 + T cells with TGF-β and IL-4 gives rise to predominantly IL-9-secreting Th9 cells (Dardalhon et al., 2008; Veldhoen et al., 2008). Th9 cells make low amounts of Th2 cytokines IL-4, IL-5, and IL-13. The levels of IL-10 produced by Th9 cells vary according to a number of reports (Chang et al., 2010; Dardalhon et al., 2008; Veldhoen et al., 2008). Th9 cells promote allergic airway inflammation (Chang et al., 2010; Staudt et al., 2010). Th9 cells play a protective role in worm expulsion as transgenic mice expressing a dominant negative form of TGF-βR fail to mount protective immune responses leading to increased worm burden (Veldhoen et al., 2008). Adoptive transfer of Th9-polarized cells can promote the development of EAE and EAU, though the inflammation that develops is distinct from Th1- or Th17-mediated inflammation (Jager et al., 2009; Tan et al., 2010). Contrary to these studies, IL-9 from Th9 cells could promote regulatory function (Elyaman et al., 2009). IL-9 can synergize with TGF-β to differentiate naı¨ve CD4+ T cells into Th17 cells (Elyaman et al., 2009). STAT6, which acts downstream of the IL-4 signal in Th2 cells, also works downstream of IL-4 in Th9 cells (Goswami et al., 2012). Even though STAT3 is activated in Th9 cells, it is dispensable for Th9 cell development (Goswami et al., 2012) and was recently demonstrated to negatively regulate IL-9 production from Th9 cells by inhibiting the activation of STAT5 (Olson et al., 2016). IL-2/STAT5 signaling reduces the expression of Bcl6 in Th9 cells and binds to the Il9 promoter to induce Th9 cell development (Bassil et al., 2014; Liao et al., 2014). Nitric oxide, which is associated with various immune disorders, augments Th9 cell differentiation that is STAT5-dependent (Niedbala et al., 2014). STAT5 also binds to the Irf4 promoter in promoting Th9 cell development (Gomez-Rodriguez et al., 2016). STAT4 inhibits the development of Th9 cells (Goswami et al., 2012). One study reported the role of STAT1 in Th9 cell development. The transcription factor IRF1, which regulates the production of Th9-secreting cytokines IL-9 and IL-21, depend on STAT1 (Vegran et al., 2014). Thus, transcription factors downstream of both IL-4 and TGF-β form a network for optimal differentiation of Th9 cells.

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3. STAT MOLECULES IN THE DEVELOPMENT OF CYTOTOXIC T CELLS In response to an infection, MHC I-restricted antigen-specific T cell clonally expand and differentiate into CD8 + cytotoxic T (Tc) cells that eliminate infected cells by the production of perforin and granzymes generating effector and memory pools of CD8+ Tc cells (Gerlach et al., 2010). IL-2 has been shown to be critical for the terminal differentiation of Tc cells (Kalia et al., 2010; Pipkin et al., 2010). The transcriptional regulation of Tc cells requires both STAT molecules and specific transcription factors (Kaech and Cui, 2012). Given below is the role of STAT molecules in the development of specific Tc cells.

3.1 Tc1 Cells To clear a viral infection, Tc cells differentiate into Tc1 cells that produce IFN-γ and TNF-α and may not act strictly as killers (Croft et al., 1994). STAT4 plays a very important role in the differentiation of Tc1 cells (Carter and Murphy, 1999). However, STAT4 has been demonstrated to be redundant to mount protective immunity against a common viral antigen (Bot et al., 2003). However, the role of STAT4 in the development of Tc1 cells may depend on the type of infection (Holz et al., 1999). The cytokine IL-27 activates STAT1 in Tc1 cells leading to enhanced cytotoxicity (Schneider et al., 2011). IL-21 also has STATdependent effects on CD8 T cells. IL-21 receptor is expressed by CD8 + T cells (Mehta et al., 2004), and CD8+ T cell effector function depends on T-bet that is induced by IL-21 via STAT1 (Sutherland et al., 2013). STAT1 signaling is also required for the direct effect of type I IFN signaling in different stages of CD8 + T cell response that results in memory cell formation after viral infection (Quigley et al., 2008). However, STAT4 is not required for the cytolytic activity of CD8 + T cells stimulated by IL-21 (Casey and Mescher, 2007). The coinhibitory molecule PD-1 attenuates the activity of Tc1 cells in tumor microenvironment by inhibiting STAT1 (Li et al., 2015). However, during proliferation after viral infection the level of STAT1 is declined in Tc1 cells (Gil et al., 2006). Expression of STAT5CA (active form of STAT5) polarizes CD8+ T cells into Tc1 cells by regulating the expression of T-bet and eomesodermin (Grange et al., 2013).

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3.2 Tc2 Cells Like their CD4 + counterparts, CD8+ T cells have the capacity to differentiate into Tc2 cells which secrete IL-4 and IL-5 (Sad et al., 1995). Tc2 cells might provide B cell help (Mosmann et al., 1997). Even though Th1 cells mount protective immune response against delayed type hypersensitivity (DTH), both Tc2 and Tc1 cells can contribute to inflammatory reactions during DTH (Li et al., 1997). The development of Tc2 cells requires STAT6 (Kaplan et al., 1999). The attenuation of the integrin VLA-4 is mediated by STAT6 signal in Tc cells (Sasaki et al., 2008). Tc1-specific STAT molecules including STAT1 and STAT4 could play inhibitory role in the development of Tc2 cells.

3.3 Tc17 Cells Akin to Tc1 and Tc2 cells, scientists have identified IL-17 secreted by CD8 + T cells known as Tc17 cells (Hamada et al., 2009). Tc17 cells could provide immunity against influenza A that is somewhat independent of perforin activity (Hamada et al., 2009). The development of Tc17 cells in vitro and in vivo requires STAT3 (Huber et al., 2009; Yen et al., 2009). Knock down of STAT3 led to attenuated production of Tc17 cells induced by IL-6 or IL-21 in concert with TGF-β (Huber et al., 2009). IL-21, but not IL-6 in combination with TGF-β polarizes Tc1 cells to Tc17 cells (Chen et al., 2016). Proliferation and survival of CD8 + T cells depend on STAT3 during effector responses against infection (Yu et al., 2013). For optimal development of Tc17 cells, both STAT1 and STAT4 are required (Ciric et al., 2009). Moreover, the switch to Tc1 cells from Tc17 cells requires STAT4 (Yeh et al., 2010). IL-27 inhibits Tc17 development through a STAT1dependent mechanism, although committed Tc17 cells are not affected by IL-27 (El-Behi et al., 2014).

3.4 Tc9 Cells Scientists have reported the existence of IL-9-secreting Tc9 cells, the counterpart of Th9 cells (Visekruna et al., 2013). Tc9 cells can promote allergic inflammation and demonstrate reduced cytotoxicity (Visekruna et al., 2013). Tc9 cells also display enhanced antitumor activity compared to Tc1 and Th1 cells (Lu et al., 2014). STAT6 is required for the development of Tc9 cells (Visekruna et al., 2013). Whether other STAT molecules are required for the development of Tc9 cells is not completely understood. The cytokines that activate specific STAT molecues in T cells are summarized in Table 1.

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4. STATs MUTATIONS RESULT IN PATIENT IMMUNODEFICIENCY STAT molecules have been implicated in immunodeficiency disorders. Severe combined immunodeficiency (SCID), one of the most severe form of primary immunodeficiency, is a combination of defective immunoglobulin production and defective T cells. Mutation of common cytokine receptor γ chain is associated with X-linked SCID (Noguchi et al., 1993). Homozygous mutation of Jak3 is observed in patients with nonX-linked SCID (Macchi et al., 1995). Complete STAT1 deficiency is associated with severe form of innate immunodeficiency with faulty type I and II interferon responses (Chapgier et al., 2006; Dupuis et al., 2003). Autosomal recessive STAT1 deficiency mimics human disease and severe viral infections and infection to BCG is observed (Liu et al., 2011). Missense P696S mutation of STAT1 in human develops into a novel STAT1 deficiency associated with impaired immune responses to both type I and II interferons that could lead to life-threatening diseases due to viral and bacterial infections (Chapgier et al., 2009). Hypermorphic autosomal STAT1 deficiency can produce reduced numbers of Th17 cells and is associated with mucocutaneous candidiasis and disseminated dimorphic yeast infections (Milner and Holland, 2013). STAT1 gain-of-function mutations have been associated with chronic mucocutaneous candidiasis, disseminated fungal infections, and IPEX-like syndrome with intact Treg function (Kumar et al., 2014; Uzel et al., 2013; van de Veerdonk et al., 2011). Autosomal STAT3 mutations result in fewer Th17 cells along with defective B and T cell memory responses leading to increased IgE levels (Ma et al., 2008; Milner et al., 2008). This syndrome known as hyperimmunoglobulin E syndrome (HIES) or Job’s syndrome is characterized by eczema, cyst-forming pneumonia, scoliosis, and boils (Mogensen, 2013). Patients with Tyk2 mutations can also show symptoms of HIES although some debate persists (Kilic et al., 2012; Minegishi et al., 2006). As CD8 + T cell memory response is regulated by STAT3, recurrent viral infections occur due to STAT3 mutation (Siegel et al., 2011). STAT2 mutation has been associated with susceptibility to viral infection (Hambleton et al., 2013). Immunodeficiency and growth failure result from recessive STAT5b deficiency (Kofoed et al., 2003). Homozygous STAT5b mutation is associated with Treg dysregulation, while some STAT5b-deficient patients show T-cell lymphopenia (Hwa et al., 2011). Autoimmunity caused by STAT5b deficiency can be attributed to downregulation of IL-17 (Laurence et al., 2007).

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5. STAT MOLECULES IN ALLERGIC INFLAMMATION A fine balance of polarized T helper cells is required for an appropriate immune response. Allergic inflammation, including asthma, atopic dermatitis, anaphylaxis, and allergic rhinitis, develops in response to inappropriate reactions to common environmental allergens. The STAT-dependent responses of T cells contribute significantly to the development of inflammation. Thus, the Jak-STAT pathway represents an attractive target for intervention of these diseases.

5.1 Jak Proteins in Allergic Inflammation Jak1/Jak3-dependent pathways play important roles in the development of lung allergic responses (Ashino et al., 2014). Jak1 and Jak2 signaling has been targeted for preclinical evaluation to treat atopic dermatitis, and the authors found that IL-17, IL-22, and MCP-1 production was attenuated (Fridman et al., 2011). In vivo Jak1 and Jak2 inhibitor blocks activation of STAT3 (Fridman et al., 2011). In a murine model of pulmonary eosinophilia blocking the Jak3 pathway resulted in attenuated inflammation (Kudlacz et al., 2008). Jak3 also mediates neutrophil chemotaxis that could affect chronic inflammatory responses (Henkels et al., 2011). However, Tyk2 has been suggested to tilt the Th1/Th2 balance toward a Th1 phenotype thereby attenuating Th2-mediated allergic inflammation (Seto et al., 2003). Tyk2-deficient mice display increased Th2 and Th9 cells, mast cells, hyper IgE, and hypereosinophilia but defective Th17 polarization (Ubel et al., 2014).

5.2 STAT1 Data from patients and animal models support a role for STAT1 in allergic disease. Epithelial cells of asthmatic patients display constitutive activation of STAT1 (Sampath et al., 1999). Activation of STAT1 is observed in CD4 + CD161 + T cells from peripheral blood in asthmatic patients (Gernez et al., 2007). In a rat model of asthma, blocking STAT1 signaling attenuates allergic inflammation (Luhrmann et al., 2010). However, mice deficient in STAT1 display restricted recruitment of antigen-specific Th1 cells in lungs after allergen challenge leading to increased inflammation as STAT1 and STAT6 differentially regulate the trafficking of Th1 and Th2 cells, respectively (Mikhak et al., 2006). In the absence of the STAT1 signal there is an altered chemokine signature in the lung evident by attenuated

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expression of CXCL9, CXCL10, CXCL16, and CXCL11 (Mikhak et al., 2006), some of which are thought to inhibit allergic inflammation (Fulkerson et al., 2004). Consistent with an inhibitory role of STAT1, STAT1 signaling inhibits IL-4/STAT6-mediated production of eotaxin (Sato et al., 2004). The STAT1 SNP rs3771300 is inversely correlated to serum IgE population in German population and could be protective for atopic sensitization (Pinto et al., 2007). IFN-γ/STAT1 signaling also leads to the resolution of goblet cell hyperplasia by inducing apoptosis of airway epithelial cells (Stout et al., 2007). Thus, although many studies support a role for STAT1 in allergic inflammation, positive or negative affects might depend upon the timing of the signal and the responsive cell types.

5.3 STAT3 STAT3 plays an important role in mediating inflammatory responses by regulating cytokine production (Schumann et al., 1996), although STAT3 single-nucleotide polymorphisms are only modestly associated with poor lung function (Litonjua et al., 2005; Wjst et al., 2009). In human airway smooth muscle cells, STAT3 is required for the expression of various chemokines after stimulation by proinflammatory cytokines (Glosson et al., 2012). In a house dust mite model of inflammation, epithelial STAT3 activates lymphocytes and is required for the accumulation of Th2 cells; in the absence of STAT3 in lung epithelial cells mice demonstrate defective recruitment of Th2 cells and eosinophils in lungs (Simeone-Penney et al., 2007). STAT3 binds to Th2 cell loci in cooperation with STAT6 and the absence of STAT3 in CD4+ T cells of STAT6VT mice leads to impaired allergic inflammation in an ovalbumin (OVA)-induced model (Stritesky et al., 2011). These mice also do not develop into spontaneous pulmonary and skin inflammation, and blepharitis. The role of STAT3 in allergic inflammation depends on their expression different tissues and organs (Lim et al., 2015). Further studies are required to ascertain the efficacy of targeting STAT3 for treating lung disorders.

5.4 STAT4 IL-12/STAT4 signaling is pivotal for Th1 responses, and it has been argued that promoting Th1 responses may be advantageous to limit allergic inflammation. STAT4 SNPs are associated with allergic inflammation.

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STAT4 T90089C SNP is positively associated with risk of allergen-specific IgE production in asthmatic patients in Korea (Park et al., 2005). In a cockroach antigen model of airway hyperreactivity (AHR), STAT4-deficient mice show defective AHR compared to STAT4-sufficient mice, even though the level of Th2 cytokines and serum IgE level are similar between the two groups (Raman et al., 2003). For the development of IL-13-mediated asthma, STAT4 plays an important role for the production IL-12-induced IFN-γ production, and subsequent development of AHR and infiltration of the lungs by inflammatory cells (Kim et al., 2010). Intranasal IFN-γ gene transfer by a recombinant replication-deficient adenovirus significantly inhibits production of IL-4-, IL-5-, and OVA-specific serum IgE, and AHR that is mediated by STAT4 (Behera et al., 2002). In contrast, one study has reported that STAT4 is required for IL-2 and IL-18-mediated reduction of AHR (Matsubara et al., 2007). Overall, these studies suggest that STAT4 could either inhibit or promote allergic inflammation.

5.5 STAT5 Cytokines including IL-2, IL-9, and TSLP activate STAT5 that also plays key role in allergic inflammation in T cells. Although STAT5 is important in many cells types involved in allergic inflammation (Bell et al., 2013), its role in T cells is largely in regulating Th2 cytokines. STAT6-independent Th2 differentiation depends on STAT5, and STAT5 is required for eosinophil lymphocyte recruitment into the airways (Takatori et al., 2005). A recent study has reported that IL-25, which promotes Th2-mediated inflammation, signals via STAT5, suggesting that STAT5 is an important regulator of inflammatory disorders (Wu et al., 2015b). STAT5 is likely important in signaling pathways including IL-9 and TSLP that have still not been well documented.

5.6 STAT6 STAT6 activated by IL-4 contributes to multiple processes including mitogenesis, Ig class switching, and T helper cell differentiation (Paul and Seder, 1994). Various STAT6 polymorphisms have been associated with multiple features of allergic inflammation in multiple ethnic groups (Glosson et al., 2012). In an OVA-induced inflammation model in mice, STAT6 deficiency resulted in the absence of lung inflammation and

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eosinophilia accompanied with a significant reduction of IL-4 and IL-5 (Miyata et al., 1999). AHR and Th2 cytokines in BAL fluid is induced by STAT6, even though lung endothelial cell VCAM-1 expression is STAT6 independent (Kuperman et al., 1998). STAT6-deficient mice fail to develop eosinophilia during AHR due to impaired eotaxin production (Hoshino et al., 2004), and IL-5 restores AHR and eosinophilia in the absence of STAT6 (Tomkinson et al., 1999). Inactivation of Tregs leads to allergic inflammation including the characteristic histology and airway remodeling in the absence of STAT6 signaling (Dorsey et al., 2013). When mouse model of Q576R polymorphism (one of the IL-4Rα polymorphisms associated with disease; Hershey et al., 1997) was developed, it was observed that even though STAT6 activation was not affected, STAT6 enhanced expression of a subset of IL-4- and IL-13-responsive genes involved in allergic inflammation (Tachdjian et al., 2009). Allergic inflammation is induced by adoptive transfer of Th2 cells in a manner that is STAT6-dependent (Mathew et al., 2001). In addition to IL-4, IL-13 plays a key role in the development of AHR in the presence and absence of inflammation. However, both these phases require IL-4Rα/STAT6 signal (Yang et al., 2001). Neutralization of IL-13 that is expressed during respiratory syncytial virus infection, a virus that exacerbates asthma (Schwarze et al., 1997), inhibits AHR, the same phenotype is observed in STAT6deficient mice (Tekkanat et al., 2001). STAT6 plays a different role in the development of chronic asthma. STAT6-deficient mice developed AHR and a number of lesions during chronic asthma, a phenotype that is completely reversed in IL-4/IL-13-double-deficient mice (Foster et al., 2003). Similarly, in a chronic fungal asthma model, STAT6-deficient mice developed AHR and peribronchial fibrosis as the chronic development of asthma was IL-13-dependent (Blease et al., 2002). STAT6 expressed by eosinophils is required for CD4+ T cell recruitment and migration of eosinophils in lung in allergic airway inflammation (Stokes et al., 2015). STAT6 has been shown to be dispensable for OVA-induced, Th2-mediated allergic inflammation, even though STAT6 is indispensable for efficient mucus production (Chapoval et al., 2011). STAT6 is also important for allergic inflammation in other organs. Mice deficient in STAT6 do not develop diarrhea induced by repeated oral challenge of OVA (Forbes et al., 2008; Kweon et al., 2000). Eosinophilic esophagitis induced by IL-5 and IL-13 requires STAT6 (Mishra and Rothenberg, 2003). Current studies are targeting STAT6 in the development of therapeutics for lung inflammation.

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6. ROLE OF STAT MOLECULES IN INTESTINAL INFLAMMATION Chronic and relapsing inflammation of the intestine is the signature of inflammatory bowel diseases (IBD) including Crohn’s disease (CD) and Ulcerative colitis (UC) (Baumgart and Sandborn, 2012; Ordas et al., 2012). Even though CD and UC share some key features, they differ in the type and the location of intestinal inflammation (Neurath, 2014). Cytokine signaling by Jak-STAT pathway or single-nucleotide polymorphisms of Jak-STAT genes increases the risk of IBD (Jostins et al., 2012; Liu et al., 2015). In the section below we discuss the involvement of STAT molecules in intestinal inflammation.

6.1 STAT1 The function of STAT1 has been investigated in intestinal inflammation. Biopsies of inflamed mucosa demonstrate activation and enhanced expression of STAT1 (Kuhbacher et al., 2001). Expression of STAT1 is enhanced in UC and CD in monocytes, neutrophils, lamina propria, and T cells (Mudter et al., 2005; Schreiber et al., 2002). Biopsies from a cohort of UC patients in noninflamed ileal pouches display a significant increase of activated STAT1 over biopsies of familial adenomatous polyposis patients and controls (Leal et al., 2010). Expression of STAT1 and STAT1-induced genes including T-bet, IRF1, IL-12 subunits is augmented in CD and UC patients (Christophi et al., 2012). STAT1 also plays a role in dextran sodium sulfate-induced colitis (Bandyopadhyay et al., 2008). In the absence of the STAT1 signal, mice show increased survival to ischemia of the small intestine (Costantino et al., 2008). Activation of STAT1 is higher in duodenal biopsies of CD patients compared to healthy volunteers (Mazzarella et al., 2003). Thus, targeting STAT1 in intestinal disorder could potentially be therapeutic.

6.2 STAT3 STAT3 is also implicated in intestinal inflammation. Activation of STAT3 is observed in both CD and UC patients (Musso et al., 2005). Initiation of the IL-6/STAT3 cascade in lamina propria T cells induces prolonged survival of pathogenic T cells leading to chronic intestinal inflammation (Atreya et al., 2000). STAT3 SNP has been associated with IBD (Khor et al., 2011). However, not all the cytokines that activate STAT3 may promote intestinal

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inflammation. IL-22 produced by Th17 cells attenuates inflammation associated with a Th2-mediated colitis via STAT3 activation in colonic epithelial cells (Sugimoto et al., 2008). STAT3 can also induce the expression of antiinflammatory cytokine IL-10 that limits colitis (Moore et al., 2001; Takeda et al., 1999). Based on these observations it has been suggested that targeting STAT3-activating cytokines could be therapeutic to treat IBD depending on the molecules present in the local microenvironment (Nguyen et al., 2015).

6.3 STAT4 Expression and function of STAT4 has been investigated for the development of intestinal inflammation. STAT4 transgenic mice immunized with DNP-KLH develop transmural colitis and STAT4 expression is enhanced in the lamina propria of the colitic mice (Wirtz et al., 1999). In a T-cell transfer model of colitis, failure of STAT4-deficient T cells to develop into the disease is evident (Simpson et al., 1998). Active CD patients display activation of STAT4 implying the potential importance of the molecule (Shale et al., 2013). Moreover, there is altered STAT4 isoform expression in mucosal biopsies and PBMCs from patients with UC and CD (Jabeen et al., 2015). However, further studies are required to assess the mechanism of how STAT4 would lead to intestinal inflammation.

6.4 STAT5 Few studies have investigated the role of STAT5 in intestinal inflammation. Overall, STAT5 is not required for a mouse model of IBD (Sheng et al., 2014), and the absence of STAT5 leads to enhanced disease susceptibility (Han et al., 2009). Yet, activation of STAT5 is attenuated in the colonic intestinal epithelial cells in CD patients (Han et al., 2006), and a STAT5 SNP rs16967637 is associated with colonic inflammation in CD (Connelly et al., 2013). Further mechanistic studies are required to delineate the function of STAT5 in T cells in IBD.

6.5 STAT6 STAT6 is also shown to play pivotal role in intestinal inflammation. STAT6 polymorphism has been associated with the pathogenesis of a subset of patients suffering from CD in Malaysian patients as well as patient cohort in Germany (Chua et al., 2016; Klein et al., 2005; Xia et al., 2003). However, the STAT6 G2964A polymorphism is not associated with IBD in

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Dutch Caucasian patients (Xia et al., 2003). However, STAT6 is activated in UC and linked to IL-13-induced apoptosis in human colon epithelial cells (Rosen et al., 2011). In a model of oxazolone-induced colitis, STAT6 is activated and regulate the expression of the tight junction protein claudin-2, IL-33, and TSLP to mediate the disease (Rosen et al., 2013). Overall, these data underline that STAT6 plays critical role in intestinal inflammation potential of STAT6 as a promising target to curb inflammation.

7. JAK-STAT MOLECULES IN AUTOIMMUNE DISEASES Jak molecules have been targeted therapeutically to treat autoimmune disorders. The key effect of these inhibitors is to down modulate the action of proinflammatory cytokines. Jak1/Jak2 has been targeted to treat rheumatoid arthritis (O’Shea et al., 2013b). Both Jak1 and Jak3 have been targeted to treat RA, IBD, and psoriasis (Fleischmann et al., 2012; van Vollenhoven et al., 2012). Various Jak inhibitors are in clinical trial to enhance safety and efficacy. To the best of our knowledge there are no Tyk2 inhibitors that have entered clinical trials yet. Below we provide the role of individual STAT molecules in autoimmunity.

7.1 STAT1 Both type 1 and type II interferons mediate their action via STAT1; yet IFN-α/β has been suggested to treat multiple sclerosis (MS), a T cellmediated, demyelinating autoimmune disease of the central nervous system (Karp et al., 2000). In the absence of STAT1, mice expressing transgenic TCR specific for MBP are susceptible to develop EAE (Nishibori et al., 2004). Paralyzed animals display increased IFN-γ production and diminished CD4 + CD25+ Tregs (Nishibori et al., 2004). In the absence of STAT1, IL-27 induces the differentiation of Th17 cells that are encephalitogenic after adoptive transfer (Peters et al., 2015). RA patients display activated STAT1 in synovial fluid mostly located with B and T cells (Kasperkovitz et al., 2004). Blocking TNF-α or type I interferon suppresses the expression of STAT1 in RA synovial macrophages; however, neutralizing TNF-α does not affect STAT1 expression in spondyloarthopathies synovial macrophages (Gordon et al., 2012). The expression and activity of STAT1 are significantly enhanced in psoriatic skin lesions (Hald et al., 2013). Mechanistically, this could be due to blocking the inhibitor of MMP-3 and regulating cell adhesion pathway in psoriasis (Lu et al., 2013).

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STAT1 has also been suggested to be important for the pathogenesis of systemic lupus erythematosus (SLE) (Dong et al., 2007). In a mouse model of lupus, STAT1 deficiency resulted in significant increase in the production of autoantibodies associated with increased IL-6 production in the kidney (Shao et al., 2015).

7.2 STAT3 Gain-of-function mutations of STAT3 result in lymphoproliferation and decreased Tregs leading to autoimmunity (Milner et al., 2015). Activation of STAT3 is observed in multiple autoimmune diseases including EAE, MS, and SLE (Frisullo et al., 2006; Harada et al., 2007; Liu et al., 2005). STAT3 is required in vivo for the development of EAE, experimental autoimmune uveoretinitis, and autoimmune pneumonitis (Harris et al., 2007; Liu et al., 2008). Increased IL-10 production correlates with SLE that is regulated by STAT3 (Hedrich et al., 2014). Activated STAT3 in SLE patients leads to epigenetic remodeling and transactivation of IL10 to express IL-10 (Hedrich et al., 2014). Ablation of SOCS3 that inhibits STAT3, in myeloid cells, leads to expanded Th1 and Th17 cell numbers resulting in EAE (Qin et al., 2012). Inhibition of STAT3 attenuates inflammation in a mouse model of RA by reducing the expression of RANKL and inflammatory cytokines (Mori et al., 2011). A single heterozygous missense substitution mutation in STAT3 has been associated with early-onset multiorgan autoimmune disease (Flanagan et al., 2014). Thus, studies suggest that STAT3 is proinflammatory, and targeting STAT3 pathway is potential therapeutic in modulating autoimmune diseases.

7.3 STAT4 STAT4 polymorphisms have been demonstrated to be a risk factor for a number of autoimmune diseases including RA and SLE in Asian and Eurpoean populations (Kobayashi et al., 2008; Korman et al., 2008; Orozco et al., 2008; Remmers et al., 2007; Zhao et al., 2013). In Korean populations, the STAT4 polymorphism has been associated with autoimmune thyroid disease and type I diabetes (T1D) (Park et al., 2011). STAT4 polymorphism is also associated with T1D in Chinese Han population (Bi et al., 2013). In Asian populations, the early-onset but not late-onset of T1D is linked with STAT4 polymorphisms (Lee et al., 2008). A GWAS study also linked STAT4 polymorphism to EAE (International Multiple Sclerosis Genetics Consortium et al., 2013). Using a cohort of

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Spanish population it has been identified that STAT4 gene polymorphism (rs7574865) is a risk factor for developing UC but not CD (Diaz-Gallo et al., 2010). However, the same STAT4 SNP leads to susceptibility to CD but not UC in Caucasian population in Germany (Glas et al., 2010). STAT4 isoforms have suggested to be noninvasive biomarkers in patients with IBD (Jabeen et al., 2015). The requirement for STAT4 in these autoimmune diseases has been examined in mice with germline mutations in the Stat4 gene. STAT4deficient mice are protected from EAE (Chitnis et al., 2001). However, studies have reported that neither IL-12 (activator of STAT4) nor IFN-γ (produced by activated STAT4) are required for the development of EAE (Cua et al., 2003; Zhang et al., 2003). Th17 cells play an important role in EAE development and may depend on STAT4 to induce the expression of encephalogenic genes. During EAE, the CNS is infiltrated with IL-17 + IFN-γ + T cells that depend on IL-23 but not STAT4 (Duhen et al., 2013). GM-CSF recruits and activates macrophages and activates microglia in the CNS during EAE (Hamilton, 2008). GM-CSF production is impaired in Stat4
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Th1 and Th17 cells, suggesting a role of STAT4 regulated production of GM-CSF to develop EAE (McWilliams et al., 2015; Pham et al., 2013). STAT4 isoforms have been demonstrated to be critical in the development of IBD (O’Malley et al., 2008). In a cohort of Chinese UC patients, there is increased expression of IL-12 induced STAT4 (Pang et al., 2007).

7.4 STAT5 The role of STAT5 in autoimmune disorders has been extensively investigated, and many of the phenotypes are linked to the function of IL-2, IL-7, and IL-15. Il2rb
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mice which have impaired IL-2/STAT5 signaling, develop autoimmune disorders (Malek et al., 2002). IL-2 deficiency leads to increased numbers of Th17 cells in vivo, resulting in autoimmunity (Laurence et al., 2007). One study demonstrated that IL-7/STAT5 signaling initiates GM-CSF production that is critical for the development of EAE (Sheng et al., 2014). Apart from IL-2, STAT5 is also activated by IL-15. Increased IL-15 has been detected in serum and CSF of MS patients (Blanco-Jerez et al., 2002), though some studies suggest if might protect from inflammation in EAE (Wu et al., 2010). IL-15-activated STAT5 limits IL-17 production that could limit the severity of EAE (Pandiyan et al., 2012). Blocking Dll4 improved the disease symptoms of EAE in mice

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associated with increased Th2/Treg cells and diminsihed STAT5 activation (Bassil et al., 2011). CD and UC patients display increased concentrations of circulating IL-15 (Liu et al., 2000). However, mice are protected from colitis in the presence of IL-15, suggesting that IL-15 suppresses inflammation in IBD (Obermeier et al., 2006). In contrast, a lack of IL-15 in colonic CD4+ T cells attenuates Foxp3 expression and diminishes STAT5 activation leading to IBD (Tosiek et al., 2016). Blocking autoimmune arthritis by using IL-1 receptor antagonist enhances Treg differentiation by STAT5 signaling (Lee et al., 2016). Proinflammatory cytokines induce the production of CXCL13 in RA, which is associated with knocked down expression of STAT5 (Kobayashi et al., 2016). In the collagen-induced arthritis model in mice, overexpression of p53 leads to increased activation of STAT5 and increased Treg numbers thereby controlling the disease in vivo (Park et al., 2013).

7.5 STAT6 Although STAT6 is generally thought to promote allergic inflammation, there are reports suggesting that it also regulates autoimmunity. In EAE, there are conflicting studies in mice and rats as to the degree that STAT6 regulates disease (Chitnis et al., 2001; Jee et al., 2001). Moreover, although statins that reduce cholesterol by inhibiting HMG-CoA reductase promote STAT6 activation that might be linked to alleviating paralysis in EAE mice (Youssef et al., 2002), other mechanisms are also possible (Weber et al., 2014). One issue that arises in the literature is a difference in phenotype between the source of two different Stat6
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models (Wang et al., 2009). Mice with targeted deletion of the first coding exon of the SH2 domain of STAT6 are resistant to EAE induction. In contrast, mice generated by deletion of amino acids 505–584 encoding the SH2 domain of STAT6 have impaired Th2 differentiation and are susceptible to develop severe EAE (Wang et al., 2009). Thus, some of the discrepancies might arise from mutant STAT6 proteins being present in the models. In RA patients, initial studies suggested unchanged expression and activation of STAT6 (Skapenko et al., 1999). Later studies suggested that STAT6 expression is heterogeneous in RA patients implying that it is expressed in multiple cell types at multiple activation states (Walker et al., 2006). In RA synovial tissue, the expression of Jak3, STAT4, and STAT6 strongly correlates with the presence of serum RF (Walker et al., 2007). Adalimumab therapy to treat RA increases the level of activated STAT6

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(Aerts et al., 2010). Overall, studies implicate STAT6 could play both proand antiinflammatory role in autoimmune diseases.

8. BLOCKING CYTOKINE SIGNALING TO TREAT DISEASE For the treatment of multiple inflammatory disorders, antibodies that block cytokines have been used in clinical trials. Jak and STAT inhibitors are also being developed to treat various inflammatory ailments (O’Shea et al., 2013a). Although it is impossible to comprehensively summarize JAKSTAT pathway inhibitors in this broad review, we have summarized some in Table 3. Tofacitinib, a Jak1 and Jak3 inhibitor, has been developed to treat RA, UC, and psoriasis (Aittomaki and Pesu, 2014). To treat RA, tofacitinib can be administered either orally or subcutaneously (Meyer et al., 2010; Mitchell and Jones, 2016). In vivo, tofacitinib ameliorates immune response in arthritis that is dependent on IFN-γ/STAT1 signaling (Ghoreschi et al., 2011). Tofacitinib also suppresses the proliferation of CD4 + T cells as well as the production of IFN-γ and IL-17 (Tanaka, 2015). While assessing the safety profile of tofacitinib, it has been observed that the Jak inhibitor could improve disease even when the RA patients are treated with methotrexate, a known DMARD (Kremer et al., 2013; van der Heijde et al., 2013). Administration of tofacitinib caused few incidences of tuberculosis, cardiovascular events, and opportunistic infections (Kremer et al., 2013). However, tofacitinib has been suggested to have a better efficacy in order to treat RA compared to methotrexate (Lee et al., 2014). Tofacitinib has been used to treat UC as well. Tofacitinib improves UC severity in a dose-dependent manner observed in an 8-week phase II clinical trial (Sandborn et al., 2012). In a study of patient-reported outcomes, tofacitinib displayed dosedependent improvement (Panes et al., 2015). Administering tofacitinib in a dose-dependent fashion in a phase 2b study improved PASI score at week 12 with as low as 2 mg twice-daily groups (Papp et al., 2012). Oral application of tofacitinib shows significant improvement vs placebo in a 16-week phase III study to treat chronic plaque psoriasis (Papp et al., 2015). In another phase III double-blinded placebo-controlled study, 10 mg of tofacitinib demonstrated therapeutic options for patients with moderate-to-severe psoriasis (Bachelez et al., 2015). Ruxolitinib, a Jak1 and Jak2 inhibitor, has been in clinical trials to treat inflammatory disorder (Mesa et al., 2012). Manufactured by Novartis and Incyte Corp., the toxicity of ruxolitinib has been studied in multiple clinical trials (Mesa, 2010). In blocking Jak1 and Jak2, ruxolitinib impairs activation

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Table 3 Targeting Jak-STAT Signaling to Treat Inflammatory Diseases Target of Jak-STAT Inhibitor Inhibition Therapeutic for

Tofacitinib

Jak1 and Jak3 Approved for RA, effective against psoriasis and IBD

Ruxolitinib

Jak1 and Jak2 Psoriasis and myleofibrosis

Baricitinib

Jak1 and Jak2 Rheumatoid arthritis

AG490

Jak2

Collagen-induced arthritis (mice)

Filgotinib

Jak1

Phase II trial to treat rheumatoid arthritis and Crohn’s disease

Pacritinib

Jak2

Phase III trial to treat myelofibrosis

Lestaurtinib

Jak2

Phase II clinical trial against acute myeloid leukemia

Momelotinib

Jak1 and Jak2 Myelofibrosis

Upadacitinib

Jak1

Phase III clinical trial against rheumatoid arthritis

GSK2586184

Jak1

Phase II clinical trial to treat psoriasis

VX-509

Jak3

Phase IIb clinical trial to treat rheumatoid arthritis

GLPG0634

Jak1

Phase II against rheumatoid arthritis and Crohn’s disease

ASP015K

Jak1 > Jak2, Jak3

Phase II against rheumatoid arthritis and psoriasis

Fusaruside

STAT1

Effective against colitis and liver disorders (mice)

Berbamine

STAT1

Efficient against EAE (mice)

Epigallocatechin3-gallate

STAT3

Ameliorates arthritis (mice)

Anatabine

STAT3

Attenuates neuroinflammation (mice)

of STAT3 by IL-6, IL-12, or IL-23 (Fridman et al., 2011; Goodman et al., 2009). The drug has been shown to be efficacious to treat psoriasis. Ruxolitinib cream administered 1% q.d and 1.5% b.i.d reduced total lesion score by more than 50% (Punwani et al., 2012). To the best of our knowledge no phase III is currently going on with ruxolitinib to treat psoriasis.

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Another Jak1 and Jak2 inhibitor, baricitinib also can be targeted against inflammatory autoimmune disorder. A 4 mg oral dose of baricitinib improves RA disease score in a phase II trial (Genovese et al., 2016). Baricitinib improves the symptoms of RA patients who are methotrexate inadequate responders in a 24-week phase 2b study (Keystone et al., 2015). In a cohort of Japanese RA patients who were on methotrexate therapy, a double-blind placebo-controlled study of baricitinib improved signs and symptoms of the patients (Tanaka et al., 2016). In another phase 2b clinical trial, a once daily dose of 8 and 10 mg baricitinib improved PASI-75 score significantly (Papp et al., 2016). Other novel Jak inhibitors are in various phases of clinical trial to treat multiple inflammatory disorder. Targeting transcription factors for therapy is complicated by a balance between efficacy and specificity. However, individual STAT family members can be targeted for clinical use that might lead to reduced side effects compared to broader spectrum JAK inhibitors.

8.1 STAT1 Inhibitor STAT1 activates expression of multiple proinflammatory genes including inducible nitric oxide synthase; cyclooxygenase in IFN-dependent fashion has been suggested to be a target for antiinflammatory therapeutics (de Prati et al., 2005). Fusaruside is a cerebroside that phosphorylates SHP-2 and sequesters STAT1 resulting in impaired STAT1/T-bet signaling and diminished colitis (Wu et al., 2012). Berbamine, an alkaloid, attenuates the severity of EAE in mice by modulating STAT1 signaling (Ren et al., 2008). Further studies targeting STAT1 inhibition are required to be used as therapeutic in inflammatory disorders.

8.2 STAT3 Inhibitor Targeting aberrantly activated STAT3 has been an approach for many types of tumors and could be used in inflammatory disease as well. AG490, a Jak2 inhibitor, reduces the severity of symptoms of collagen induced arthritis in mice by decreasing the frequency of STAT3+ T cells (Park et al., 2014b). Epigallocatechin-3-gallate, a component of green tea, ameliorates arthritis by inhibiting STAT3 (Yang et al., 2014). A small molecule inhibitor of STAT3, ORLL-NIH001, attenuates the severity of uveitis by preventing the expansion of Th17 cells (Yu et al., 2012). Another STAT3 inhibitor, STA-21, also protects mice from experimental model of rheumatoid arthritis by attenuating the number of Th17 cells and enhancing Treg cell population

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(Park et al., 2014a). Anatabine, an alkaloid, reduces TNF-α and IL-6 and inhibits STAT3 phosphorylation in attenuating neuroinflammation (Paris et al., 2013). Metformin, which is used to treat type 2 diabetes, improves IBD by inhibiting the expression of STAT3 and enhancing Foxp3 expression (Lee et al., 2015).

8.3 STAT4 Inhibitor STAT4 inhibition could block cell-mediated inflammation. Soluble cinnamon bark extract administered orally prevents STAT4 activation and attenuates IFN-γ production in murine T cells (Lee et al., 2011). Further studies would underline the efficiency of targeting STAT4 to treat inflammatory disorder.

8.4 STAT5 Inhibitor Most of the STAT5 inhibitors have shown promise as antitumor agents (Muller et al., 2008; Nam et al., 2012; Nelson et al., 2011). Further studies are required to understand the implication of blocking STAT5 to be therapeutic against inflammation.

8.5 STAT6 Inhibitor Few STAT6 inhibitors have been developed to treat inflammatory diseases. In bronchial smooth muscle cells, a novel STAT6 inhibitor AS1517499 inhibited Ca2+ sensitization of smooth muscle contraction (Chiba et al., 2009b). Blocking STAT6 activation in epithelial cells by using small molecule inhibitors impairs eosinophil infiltration as eotaxin-3 production is impaired (Zhou et al., 2012). A couple of other STAT6 inhibitors, YM-341619 and AS1810722, have been suggested as potential therapeutics against asthma (Nagashima et al., 2008, 2009). In human bronchial smooth muscle cells, Leflunomide has been demonstrated to inhibit IL-13-induced STAT6 activation (Chiba et al., 2009a). In the future, further studies are required to assess the potential of STAT6 inhibitors in treating inflammatory disorder.

9. CONCLUSION The evolutionarily conserved Jak-STAT pathway is used by cytokines, growth factors, and similar molecules. Extensive research of the signaling cascade has enhanced our understanding of human disease by

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applying the knowledge gained from basic science research to translational research. This has led to the development of new class of therapeutics with more advances in the pipeline. Histone epigenetic marks have been mapped for better understanding of chromatin accessibility and correlation with STAT binding. T cell epigenome and cytokine signaling have been studied in detail to assess the differentiation and plasticity of CD4+ T cells (O’Shea and Paul, 2010). It is important to understand the nature of chromatin modification and T cell differentiation as well as the control of epigenetic marks after the recruitment of STAT proteins. Chromatin immunoprecipitationsequencing techniques have defined epigenetic signature and STATdependent gene expression (Wei et al., 2010). Thus, STAT molecules that maintain the epigenome of T cells could be targeted for future therapeutics. Apart from the epigenetic control of gene expression other regulators control the expression of Jak-STAT molecules. MicroRNA (miRNA), 22 nt small single-stranded RNA, regulates gene expression by binding to 30 -UTR of target mRNA (Bartel, 2009) and can regulate the Jak-STAT pathway. For example, miR-135b suppresses IL-13-induced collagen expression by targeting STAT6 (O’Reilly et al., 2016). Several other miRNA regulate the expression of Jak-STAT molecules in cancer indicating the fine tuning between Jak-STAT signaling and miRNA expression. Conversely, miRNA expression in T cells is also regulated by STAT molecules (Lu et al., 2010; van der Fits et al., 2011). Therefore, regulating the expression of miRNA might modulate the expression of STAT molecules leading to the development of disease-specific therapeutics. In this review we have discussed the role of Jak-STAT signaling in T cell differentiation as well as the importance of this signaling cascade in various diseases. Further studies to link epigenetic control, miRNA expression and the activation of Jak-STAT molecules would pave targeted therapies to treat various inflammatory disorders.

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