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Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5.
Nat Immunol. 2011 Mar; 12(3):247-54
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18 Feb 2011
Philip Murphy
F1000 Immunology
National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD, USA.
F1000 Immunology
National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD, USA.
Wuzhou Wan
F1000 Immunology
National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD, USA.
F1000 Immunology
National Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD, USA.
Novel Drug Target
DOI: 10.3410/f.8369956.8815054
It is known that lack of interleukin 2 (IL-2) results in severe autoimmune disease in mice, and that IL-2 can limit IL-17 production, but the mechanism is not clear. This paper shows that signal transducer and activator of transcription 3 (STAT3) in T cells is necessary for the inflammatory colitis...Continue reading
It is known that lack of interleukin 2 (IL-2) results in severe autoimmune disease in mice, and that IL-2 can limit IL-17 production, but the mechanism is not clear. This paper shows that signal transducer and activator of transcription 3 (STAT3) in T cells is necessary for the inflammatory colitis associated with IL-2 deficiency, and IL-2 inhibits IL-17 expression through enhanced binding of STAT5 to the Il17 locus. This outstanding study by Yang et al. reports a new model of Th17 differentiation, a critical lineage involved in anti-microbial host defense and pathogenesis of autoimmune diseases.
This is the first study to show that suppression of inhibitory cytokine-signaling pathways on T-cell differentiation, in this case IL-2/STAT5, could lead to Th17 differentiation, despite minimal presence of the positive inducers IL-6/STAT3. Although IL-2 has a profound effect on regulatory T cell (Treg) generation, deletion of STAT3 did not totally reverse Treg deficiency, but rescued excessive Th17 cell-mediated colitis associated with IL-2 deficiency, indicating the in vivo significance of IL-2-mediated inhibition of Th17 differentiation, a process clearly independent of Foxp3.
This article opens up a new area of immune regulation as it provides data suggesting that our view of signalling pathways underlying T-cell differentiation should be graded and quantitative, rather than binary and qualitative. By identifying both the positive and negative regulators involved in T-cell differentiation, opportunities have been created to develop new therapies against autoimmune diseases using these factors as targets. For further reading please see refs {1-3}.
This is the first study to show that suppression of inhibitory cytokine-signaling pathways on T-cell differentiation, in this case IL-2/STAT5, could lead to Th17 differentiation, despite minimal presence of the positive inducers IL-6/STAT3. Although IL-2 has a profound effect on regulatory T cell (Treg) generation, deletion of STAT3 did not totally reverse Treg deficiency, but rescued excessive Th17 cell-mediated colitis associated with IL-2 deficiency, indicating the in vivo significance of IL-2-mediated inhibition of Th17 differentiation, a process clearly independent of Foxp3.
This article opens up a new area of immune regulation as it provides data suggesting that our view of signalling pathways underlying T-cell differentiation should be graded and quantitative, rather than binary and qualitative. By identifying both the positive and negative regulators involved in T-cell differentiation, opportunities have been created to develop new therapies against autoimmune diseases using these factors as targets. For further reading please see refs {1-3}.
References
1.
Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation.
Immunity 2007 Mar; 3(26):371-81
PMID: 17363300
2.
The biology of interleukin-2.
Annu Rev Immunol 2008; (26):453-79
PMID: 18062768
3.
Distinct roles of helper T-cell subsets in a systemic autoimmune disease.
Blood 2009 Jan 8; 2(113):389-95
PMID: 18815283
Disclosures
None declared
Add Comment
Murphy P and Wan W: F1000Prime Recommendation of [Yang XP et al., Nat Immunol 2011, 12(3):247-54]. In F1000Prime, 18 Feb 2011; DOI: 10.3410/f.8369956.8815054. F1000Prime.com/8369956#eval8815054
01 Mar 2011
DOI: 10.3410/f.8369956.9066054
This fascinating study delineates a novel model of T cell differentiation, which is the balance of two cytokine signaling pathways (IL-6/STAT3 versus IL-2/STAT5) and the competition of STAT3 and STAT5 on the genetic locus encoding interleukin (IL)-17, thus determining the fate of TH17 cells and the...Continue reading
This fascinating study delineates a novel model of T cell differentiation, which is the balance of two cytokine signaling pathways (IL-6/STAT3 versus IL-2/STAT5) and the competition of STAT3 and STAT5 on the genetic locus encoding interleukin (IL)-17, thus determining the fate of TH17 cells and the severity of related autoimmune diseases.
IL-17-producing helper T cells (TH17 cells) play a crucial role in autoimmune diseases, e.g. autoimmune hepatitis, inflammatory bowel disease, and psoriasis. It is well recognized that IL-2 inhibits the differentiation of TH17 cells. However, details about the molecular mechanism of how IL-2 inhibits TH17 cell differentiation and IL-17 production still remain obscure. Previous work based on IL-2-/- mice on a BALB/c background that suffer from autoimmune hemolytic anemia suggests that in some settings, IL-2 inhibits expression of IL-17 via high expression of Foxp3 and decreased RORgammat.
In the present study, Yang XP and colleagues found that IL-2-dependent negative regulation of IL-17 expression is largely neither Foxp3- nor RORgammat-dependent. They found that IL-2 significantly decreased IL-17 expression in T cells from normal or Foxp3-mutant mice. In addition, IL-2 still is able to inhibit IL-17 expression when T cells have supraphysiological amounts of RORgammat.
They provide data showing that two transcription factors, STAT3 and STAT5, are critical for TH17 cell differentiation and the anti-IL-17 effect of IL-2. Disruption of the IL-2 gene in mice leads to serious colitis due to enhanced production of TH17 cells. Deletion of STAT3 in IL-2-/- mice (IL-2 and STAT3 double-knockout mice) improved IL-2 deficiency-related pathology in association with a prolonged lifespan. Further, the authors found that the inhibitory effect of IL-2 on IL-17 expression is completely STAT5-dependent. Constitutively active STAT5 was sufficient to inhibit IL-17 production, whereas IL-2 totally lost its inhibitory effect for IL-17 expression in T cells from mice with a disrupted STAT5 gene.
In addition, they found that IL-2 did not influence IL-6-dependent STAT3 activation, indicating direct effects of IL-2/STAT5 on the Il17a-Il17f gene locus. Using a method named chromatin-immunoprecipitation followed by massive parallel sequencing (ChIP-seq), the authors confirmed that there were six sites associated with binding of both STAT3 and STAT5 in the Il17a-Il17f promoter region. STAT5 binding correlated with significantly less binding of STAT3 at all six sites associated with Il17a and only one of two sites associated with Il17f. Finally, they show that recruitment of STAT5 to the Il17 locus is associated with less histone H3 acetylation and trimethylation of histone H3 Lys4, more recruitment of transcriptional repressor NCoR2, thus decreasing gene transcription.
The study shows impressively that two proteins of the STAT family have competitive binding activity to the same promoter elements, thereby exerting opposing functions. This means, when we identify a gene locus as a potential target for therapeutic interference, one must bear in mind that different transcription factors might use the same site to attack or defend your health. Thus, these interesting findings will definitely have an implication in the identification of drug targets and the design of useful therapeutic strategies against autoimmune and other human diseases. For further reading, please see {1-5}.
IL-17-producing helper T cells (TH17 cells) play a crucial role in autoimmune diseases, e.g. autoimmune hepatitis, inflammatory bowel disease, and psoriasis. It is well recognized that IL-2 inhibits the differentiation of TH17 cells. However, details about the molecular mechanism of how IL-2 inhibits TH17 cell differentiation and IL-17 production still remain obscure. Previous work based on IL-2-/- mice on a BALB/c background that suffer from autoimmune hemolytic anemia suggests that in some settings, IL-2 inhibits expression of IL-17 via high expression of Foxp3 and decreased RORgammat.
In the present study, Yang XP and colleagues found that IL-2-dependent negative regulation of IL-17 expression is largely neither Foxp3- nor RORgammat-dependent. They found that IL-2 significantly decreased IL-17 expression in T cells from normal or Foxp3-mutant mice. In addition, IL-2 still is able to inhibit IL-17 expression when T cells have supraphysiological amounts of RORgammat.
They provide data showing that two transcription factors, STAT3 and STAT5, are critical for TH17 cell differentiation and the anti-IL-17 effect of IL-2. Disruption of the IL-2 gene in mice leads to serious colitis due to enhanced production of TH17 cells. Deletion of STAT3 in IL-2-/- mice (IL-2 and STAT3 double-knockout mice) improved IL-2 deficiency-related pathology in association with a prolonged lifespan. Further, the authors found that the inhibitory effect of IL-2 on IL-17 expression is completely STAT5-dependent. Constitutively active STAT5 was sufficient to inhibit IL-17 production, whereas IL-2 totally lost its inhibitory effect for IL-17 expression in T cells from mice with a disrupted STAT5 gene.
In addition, they found that IL-2 did not influence IL-6-dependent STAT3 activation, indicating direct effects of IL-2/STAT5 on the Il17a-Il17f gene locus. Using a method named chromatin-immunoprecipitation followed by massive parallel sequencing (ChIP-seq), the authors confirmed that there were six sites associated with binding of both STAT3 and STAT5 in the Il17a-Il17f promoter region. STAT5 binding correlated with significantly less binding of STAT3 at all six sites associated with Il17a and only one of two sites associated with Il17f. Finally, they show that recruitment of STAT5 to the Il17 locus is associated with less histone H3 acetylation and trimethylation of histone H3 Lys4, more recruitment of transcriptional repressor NCoR2, thus decreasing gene transcription.
The study shows impressively that two proteins of the STAT family have competitive binding activity to the same promoter elements, thereby exerting opposing functions. This means, when we identify a gene locus as a potential target for therapeutic interference, one must bear in mind that different transcription factors might use the same site to attack or defend your health. Thus, these interesting findings will definitely have an implication in the identification of drug targets and the design of useful therapeutic strategies against autoimmune and other human diseases. For further reading, please see {1-5}.
References
1.
Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective.
Nat Rev Immunol 2009 Dec; 12(9):883-9
PMID: 19935807
2.
Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis.
Immunity 2010 May 28; 5(32):605-15
PMID: 20493732
3.
TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.
Nature 2008 May 8; 7192(453):236-40
PMID: 18368049
4.
Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells.
Immunity 1999 Feb; 2(10):249-59
PMID: 10072077
5.
Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation.
Immunity 2010 Jun 25; 6(32):840-51
PMID: 20620946
Disclosures
None declared
Dooley S and Weng H: F1000Prime Recommendation of [Yang XP et al., Nat Immunol 2011, 12(3):247-54]. In F1000Prime, 01 Mar 2011; DOI: 10.3410/f.8369956.9066054. F1000Prime.com/8369956#eval9066054
21 Mar 2011
Novel Drug Target
DOI: 10.3410/f.8369956.9380054
This is a highly interesting study by Yang et al. which further characterizes the pleiotropic tolerogenic effects of interleukin (IL)-2. The authors elegantly describe how IL-2 can directly inhibit IL-17A expression independently of its effects on the T regulatory cell-associated transcription factor...Continue reading
This is a highly interesting study by Yang et al. which further characterizes the pleiotropic tolerogenic effects of interleukin (IL)-2. The authors elegantly describe how IL-2 can directly inhibit IL-17A expression independently of its effects on the T regulatory cell-associated transcription factor Foxp3.
Firstly, the authors demonstrate that T cell-specific STAT3 deficiency can rescue the colitogenic phenotype of IL-2 deficient mice. This extends previous reports that STAT3 activation is a critical factor in T helper (Th) 17 cell differentiation {1}, but also suggests a role for STAT3 as an important downstream target of IL-2 pro-tolerogenic signals. Further characterization of the interplay between STAT3 and IL-2 signalling reveals the most novel aspect of this study wherein the authors describe the opposing functions of the related STAT3 and STAT5 transcription factors at the IL-17a-IL-17f locus. The demonstration that IL-2-mediated STAT5 activation can repress STAT3-mediated transcription and binds at the same regions within the IL-17a-IL-17f locus raises important issues as to the interplay between these transcription factors at specific loci. As the authors point out, both transcription factors have previously been shown to act in a complementary fashion to drive expression of a number of genes {2}; this begs the question as to what defines the mechanisms through which these STAT family members can have such opposing effects? Also, given the recently reported, and perhaps surprising, role of STAT3 in the generation of Th2 responses {3}, one wonders what are the consequences, if any, of STAT5 activation in this context. Further investigation of such questions will undoubtedly reveal important insights into the relative roles of cytokine signalling pathways in directing the fate of T cell responses and will be of great significance to efforts to target the IL-2/Th17 cell axis in autoimmune disease.
Firstly, the authors demonstrate that T cell-specific STAT3 deficiency can rescue the colitogenic phenotype of IL-2 deficient mice. This extends previous reports that STAT3 activation is a critical factor in T helper (Th) 17 cell differentiation {1}, but also suggests a role for STAT3 as an important downstream target of IL-2 pro-tolerogenic signals. Further characterization of the interplay between STAT3 and IL-2 signalling reveals the most novel aspect of this study wherein the authors describe the opposing functions of the related STAT3 and STAT5 transcription factors at the IL-17a-IL-17f locus. The demonstration that IL-2-mediated STAT5 activation can repress STAT3-mediated transcription and binds at the same regions within the IL-17a-IL-17f locus raises important issues as to the interplay between these transcription factors at specific loci. As the authors point out, both transcription factors have previously been shown to act in a complementary fashion to drive expression of a number of genes {2}; this begs the question as to what defines the mechanisms through which these STAT family members can have such opposing effects? Also, given the recently reported, and perhaps surprising, role of STAT3 in the generation of Th2 responses {3}, one wonders what are the consequences, if any, of STAT5 activation in this context. Further investigation of such questions will undoubtedly reveal important insights into the relative roles of cytokine signalling pathways in directing the fate of T cell responses and will be of great significance to efforts to target the IL-2/Th17 cell axis in autoimmune disease.
References
1.
Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis.
Immunity 2010 May 28; 5(32):605-15
PMID: 20493732
2.
Reciprocal effects of STAT5 and STAT3 in breast cancer.
Mol Cancer Res 2009 Jun; 6(7):966-76
PMID: 19491198
3.
The transcription factor STAT3 is required for T helper 2 cell development.
Immunity 2011 Jan 28; 1(34):39-49
PMID: 21215659
Disclosures
None declared
Fallon P and Walsh P: F1000Prime Recommendation of [Yang XP et al., Nat Immunol 2011, 12(3):247-54]. In F1000Prime, 21 Mar 2011; DOI: 10.3410/f.8369956.9380054. F1000Prime.com/8369956#eval9380054
08 Jun 2011
Allen Ho
F1000 Immunology
University at Buffalo, The State University of New York,
Buffalo, NY, USA.
F1000 Immunology
University at Buffalo, The State University of New York,
Buffalo, NY, USA.
New Finding
DOI: 10.3410/f.8369956.11976054
The development and expansion of interleukin (IL)-17-producing T helper (Th)17 cells requires various cytokines, including transforming growth factor (TGF)-beta, IL-6, IL-21 and IL-23. These, in turn, regulate downstream transcription factors, STAT3 and RORgammat, which are considered 'master regulators'...Continue reading
The development and expansion of interleukin (IL)-17-producing T helper (Th)17 cells requires various cytokines, including transforming growth factor (TGF)-beta, IL-6, IL-21 and IL-23. These, in turn, regulate downstream transcription factors, STAT3 and RORgammat, which are considered 'master regulators' of Th17 differentiation. Conversely, IL-2 via STAT5 inhibits Th17 differentiation. This report by Yang et al. elegantly identifies an important and surprising molecular mechanism by which IL-2 and STAT5 impact STAT3 and, thereby, modulate IL-17 expression at the level of the il17a promoter. Since IL-2 is important in the generation of T-regulatory cells (Tregs), this IL-2 / STAT5-mediated regulation of STAT3 may be vital in maintaining the balance between Tregs and Th17 cells in vivo. Moreover, these findings provide a glimpse into the relatively less understood mechanisms of plasticity among different Th cell lineages.
This group previously showed that IL-2 signaling via STAT5 antagonizes Th17 cell generation {1}. Yang et al. demonstrate here that STAT5 mediates this process by directly inhibiting STAT3 binding at the il17a gene locus, a critical event for IL-17 transcription. They show that IL-2 deficiency in mice leads to inflammatory colitis combined with an increase in Th17 cells. Deletion of STAT3 in these mice reverses this phenotype, underscoring the importance of STAT3 regulation in Th17 cells. They did not observe any differences in the absolute number of forkhead box P3 (Foxp3)+ CD4+ T cells, and deletion of Foxp3 in mice (scurfy mice) did not alter IL-2/STAT5-mediated inhibition of Th17 cell generation. The authors also did not observe a significant effect on the proportion of RORgammat+ cells upon STAT5 deletion or IL-2 neutralization, suggesting a RORgammat-independent mechanism. To identify mechanisms underlying IL-2-mediated inhibition of Th17 responses, chromatin immunoprecipitation-sequencing (CHIP-Seq) was used to test the possibility of direct effects of STAT5 on the il17a promoter. Interestingly, STAT5 could bind to the IL-17 proximal promoter as well as the distal sites, which overlap with putative STAT3 binding sites. They further observed a reciprocal pattern of STAT5 and STAT3 binding to the IL-17 promoter following IL-2 stimulation, confirming the competitive inhibition model. Furthermore, IL-2 treatment of Th17 cells led to epigenetic modifications at the IL-17 locus as observed by decreased p300-binding, reduction in the histone-3 acetylation and the recruitment of a histone deacetylase, NCoR2. Thus, competitive binding between STAT3 and STAT5 underlies their reciprocal effects on IL-17 expression.
Though epigenetic changes and transcription factor binding at conserved non-coding sites is common in gene regulation, competitive inhibition at the promoter sites is a somewhat novel mechanism of regulation. This report establishes one such mechanism in Th17 cells and provides a strong base for further investigation in other lineages.
This group previously showed that IL-2 signaling via STAT5 antagonizes Th17 cell generation {1}. Yang et al. demonstrate here that STAT5 mediates this process by directly inhibiting STAT3 binding at the il17a gene locus, a critical event for IL-17 transcription. They show that IL-2 deficiency in mice leads to inflammatory colitis combined with an increase in Th17 cells. Deletion of STAT3 in these mice reverses this phenotype, underscoring the importance of STAT3 regulation in Th17 cells. They did not observe any differences in the absolute number of forkhead box P3 (Foxp3)+ CD4+ T cells, and deletion of Foxp3 in mice (scurfy mice) did not alter IL-2/STAT5-mediated inhibition of Th17 cell generation. The authors also did not observe a significant effect on the proportion of RORgammat+ cells upon STAT5 deletion or IL-2 neutralization, suggesting a RORgammat-independent mechanism. To identify mechanisms underlying IL-2-mediated inhibition of Th17 responses, chromatin immunoprecipitation-sequencing (CHIP-Seq) was used to test the possibility of direct effects of STAT5 on the il17a promoter. Interestingly, STAT5 could bind to the IL-17 proximal promoter as well as the distal sites, which overlap with putative STAT3 binding sites. They further observed a reciprocal pattern of STAT5 and STAT3 binding to the IL-17 promoter following IL-2 stimulation, confirming the competitive inhibition model. Furthermore, IL-2 treatment of Th17 cells led to epigenetic modifications at the IL-17 locus as observed by decreased p300-binding, reduction in the histone-3 acetylation and the recruitment of a histone deacetylase, NCoR2. Thus, competitive binding between STAT3 and STAT5 underlies their reciprocal effects on IL-17 expression.
Though epigenetic changes and transcription factor binding at conserved non-coding sites is common in gene regulation, competitive inhibition at the promoter sites is a somewhat novel mechanism of regulation. This report establishes one such mechanism in Th17 cells and provides a strong base for further investigation in other lineages.
References
1.
Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation.
Immunity 2007 Mar; 3(26):371-81
PMID: 17363300
Disclosures
None declared
Gaffen S, Ho A and Garg A: F1000Prime Recommendation of [Yang XP et al., Nat Immunol 2011, 12(3):247-54]. In F1000Prime, 08 Jun 2011; DOI: 10.3410/f.8369956.11976054. F1000Prime.com/8369956#eval11976054
F1000Prime Recommendations, Dissents and Comments for [Yang XP et al., Nat Immunol 2011, 12(3):247-54]. In F1000Prime, 20 May 2013; F1000Prime.com/8369956
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Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production. Here we found that deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency. Whereas STAT3 induced IL-17 and the transcription factor RORγt and inhibited the transcription factor Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. STAT3 and STAT5 bound to multiple common sites across the locus encoding IL-17. The induction of STAT5 binding by IL-2 was associated with less binding of STAT3 at these sites and the inhibition of associated active epigenetic marks. 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL-17-producing helper T cell (T(H)17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.
DOI: 10.1038/ni.1995
PMID: 21278738
