Stat transcription factors in immunoregulation and autoimmune disease View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2009-2017

FUNDING AMOUNT

24580843 USD

ABSTRACT

Cytokines regulate cellular growth and differentiation, along with immune and inflammatory responses. They are critical in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, SLE, IBD, psoriasis, allergy and asthma. Targeting cytokines and cytokine signaling has led to successful new strategies for treating these diseases, underscoring the need to better understand the molecular basis of cytokine action as it relates to the pathogenesis of immune-mediated disease. A critical means by which cytokines exert their effect is activation of receptor-associated Janus kinases, or JAKs, and the activation of a family of transcription factors called STATs; this has been the focus of our work for the last two decades. One important action of cytokines in which STATs play a key role is the differentiation of different subsets of lymphocytes to attain distinct fates, and this too has been a longstanding interest of the lab. The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct in various tissues, has not been fully ascertained. We used mouse models of paralog deficiency to demonstrate that they are not equivalent for CD4+ helper T cells. We found that STAT5B is dominant for both effector and regulatory responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output confirms that STAT5B has far greater impact but, surprisingly, the data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, relative abundance of STAT5 imposes functional specificity (or dominance) in the face of widespread structural homology. In related collaborative work, we found that the Stat5a/b locus is subject to additional lineage-specific transcriptional control. CRISPR/Cas9-mediated genome editing was used to delete these sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels and a concomitant reduction of STAT5-dependent gene expression. We have previously shown that STATs, especially STAT1 and STAT4, are important drivers of expression of a lineage defining transcription factor (LDTF) in T helper 1 (Th1) cells termed T-bet encoded by Tbx21). IFN-g, a member of a large family of anti-pathogenic and anti-tumor IFNs, acting through STAT1 induces T-bet, which in turn supports IFN-g production in a feed-forward manner. In a study published this year, we showed that a cell-intrinsic role of T-bet determines how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-g aberrantly induced a type I IFN transcriptomic program in T cells. Specifically, T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, this work identified an unanticipated function of a well-known LDTF. In addition to promoting Th1 effector commitment and production of the signature cytokine IFN-g, T-bet acts as a repressor in differentiated Th1 cells to prevent aberrant autocrine type I IFN and downstream signaling. Blimp-1 (encoded by Prdm1) is an LDTF expressed in differentiated effector T cells that extinguishes the fate of T follicular helper cells and limits autoimmunity. We found unexpectedly that STAT3 and not STAT6 plays a critical role in regulating Blimp-1 in TH2 cells. Furthermore, we found that the cytokine interleukin-10 (IL-10) acted directly on TH2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3. Moreover, we found that Blimp-1 and STAT3 amplified IL-10 production in TH2 cells, creating a strong autoregulatory loop that enhanced Blimp-1 expression. Increased Blimp-1 in T cells antagonized STAT5-regulated cell cycle and antiapoptotic genes to limit cell expansion. By contrast, we found a very distinct mode of regulation of Blimp-1 in Th17 cells compared to Th2 cells. Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of Th17 cells. We found that IL-23 induces Blimp-1 and peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome-wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORt, STAT-3, and p300 at the Il23r, Il17a/f, and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. An important transcription factor that antagonizes effector differentiation of T cells is Bach2. In collaboration, we extended our previous work on Bach2 in CD4 T cells to study its role on the differentiation state of CD8 T cells. We found that the BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 sites to Jun family signal-dependent transcription factors. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation, but in effector cells reduced expression enabling unrestrained induction of TCR-driven programs. Polymorphisms of the BACH2 locus are associated with multiple autoimmune diseases including rheumatoid arthritis, lupus, diabetes, IBD, asthma, multiple sclerosis and other diseases. In related work, we found that BACH2 mutations underlie a previously unrecognized Mendelian monogenic primary immunodeficiency manifested by immunodeficiency and autoimmunity. Innate lymphoid cells (ILCs) represent a subset of cells that play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4 T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We found that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naive CD4 T cells during Th cell differentiation during parasite infection. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways. During this year, we have investigated the role of STAT5 in ILCs and the relationship between ILC poised epigenomes and acute activation in terms of rapid regulation of gene expression. In related epigenomic work, we investigated the role of histone variants in regulation of transcription. We found that mH2A1.2 is required for gene expression and cellular differentiation. Moreover, H3K27 acetylation was found to be dependent upon mH2A1.2, indicating a role for this factor in enhancer activation. More... »

URL

http://projectreporter.nih.gov/project_info_description.cfm?aid=9572252

Related SciGraph Publications

  • 2017-07. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency in NATURE IMMUNOLOGY
  • 2017-03-22. Mechanisms and consequences of Jak-STAT signaling in the immune system in NATURE IMMUNOLOGY
  • 2016-07. BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers in NATURE IMMUNOLOGY
  • 2016-01. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases in NATURE REVIEWS RHEUMATOLOGY
  • 2015-09. EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion in SCIENTIFIC REPORTS
  • 2015-04. Super-enhancers delineate disease-associated regulatory nodes in T cells in NATURE
  • 2014-12. BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • 2014-07-21. Enhancing the understanding of asthma in NATURE IMMUNOLOGY
  • 2014. Helper T Cell Plasticity: Impact of Extrinsic and Intrinsic Signals on Transcriptomes and Epigenomes in TRANSCRIPTIONAL CONTROL OF LINEAGE DIFFERENTIATION IN IMMUNE CELLS
  • 2013-06. BACH2 represses effector programs to stabilize Treg-mediated immune homeostasis in NATURE
  • 2013-03-06. Autoimmunity: Rubbing salt in the wound in NATURE
  • 2013-03. Back to the future: oral targeted therapy for RA and other autoimmune diseases in NATURE REVIEWS RHEUMATOLOGY
  • 2012-12. New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer in JOURNAL OF TRANSLATIONAL MEDICINE
  • 2012-06. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells in NATURE IMMUNOLOGY
  • 2011-12. Summit on cell therapy for cancer: The importance of the interaction of multiple disciplines to advance clinical therapy in JOURNAL OF TRANSLATIONAL MEDICINE
  • 2011-04. Genomic views of STAT function in CD4+ T helper cell differentiation in NATURE REVIEWS IMMUNOLOGY
  • 2011-03. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5 in NATURE IMMUNOLOGY
  • 2010-10. Generation of pathogenic TH17 cells in the absence of TGF-β signalling in NATURE
  • 2009-12. Immune modulation: Turncoat regulatory T cells in NATURE MEDICINE
  • 2009-11. The functional plasticity of T cell subsets in NATURE REVIEWS IMMUNOLOGY
  • 2009-04. Selectivity and therapeutic inhibition of kinases: to be or not to be? in NATURE IMMUNOLOGY
  • 2009-03. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17–producing effector T helper cells in vivo in NATURE IMMUNOLOGY
  • 2008-12. New complexities in helper T cell fate determination and the implications for autoimmune diseases in MODERN RHEUMATOLOGY
  • 2008-09-11. T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance in NATURE
  • 2008-07. Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques in MUCOSAL IMMUNOLOGY
  • 2008-06. Th17 cells: a new fate for differentiating helper T cells in IMMUNOLOGIC RESEARCH
  • 2008-05. T cell heterogeneity: firmly fixed, predominantly plastic or merely malleable? in NATURE IMMUNOLOGY
  • 2008-04-10. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome in NATURE
  • 2008-03. Interleukin-22: a sheep in wolf's clothing in NATURE MEDICINE
  • 2007-12. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10 in NATURE IMMUNOLOGY
  • 2007-01. T cell–directed therapies: lessons learned and future prospects in NATURE IMMUNOLOGY
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The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct in various tissues, has not been fully ascertained. We used mouse models of paralog deficiency to demonstrate that they are not equivalent for CD4+ helper T cells. We found that STAT5B is dominant for both effector and regulatory responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output confirms that STAT5B has far greater impact but, surprisingly, the data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, relative abundance of STAT5 imposes functional specificity (or dominance) in the face of widespread structural homology. In related collaborative work, we found that the Stat5a/b locus is subject to additional lineage-specific transcriptional control. CRISPR/Cas9-mediated genome editing was used to delete these sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels and a concomitant reduction of STAT5-dependent gene expression. We have previously shown that STATs, especially STAT1 and STAT4, are important drivers of expression of a lineage defining transcription factor (LDTF) in T helper 1 (Th1) cells termed T-bet encoded by Tbx21). IFN-g, a member of a large family of anti-pathogenic and anti-tumor IFNs, acting through STAT1 induces T-bet, which in turn supports IFN-g production in a feed-forward manner. In a study published this year, we showed that a cell-intrinsic role of T-bet determines how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-g aberrantly induced a type I IFN transcriptomic program in T cells. Specifically, T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, this work identified an unanticipated function of a well-known LDTF. In addition to promoting Th1 effector commitment and production of the signature cytokine IFN-g, T-bet acts as a repressor in differentiated Th1 cells to prevent aberrant autocrine type I IFN and downstream signaling. Blimp-1 (encoded by Prdm1) is an LDTF expressed in differentiated effector T cells that extinguishes the fate of T follicular helper cells and limits autoimmunity. We found unexpectedly that STAT3 and not STAT6 plays a critical role in regulating Blimp-1 in TH2 cells. Furthermore, we found that the cytokine interleukin-10 (IL-10) acted directly on TH2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3. Moreover, we found that Blimp-1 and STAT3 amplified IL-10 production in TH2 cells, creating a strong autoregulatory loop that enhanced Blimp-1 expression. Increased Blimp-1 in T cells antagonized STAT5-regulated cell cycle and antiapoptotic genes to limit cell expansion. By contrast, we found a very distinct mode of regulation of Blimp-1 in Th17 cells compared to Th2 cells. Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of Th17 cells. We found that IL-23 induces Blimp-1 and peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome-wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORt, STAT-3, and p300 at the Il23r, Il17a/f, and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. An important transcription factor that antagonizes effector differentiation of T cells is Bach2. In collaboration, we extended our previous work on Bach2 in CD4 T cells to study its role on the differentiation state of CD8 T cells. We found that the BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 sites to Jun family signal-dependent transcription factors. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation, but in effector cells reduced expression enabling unrestrained induction of TCR-driven programs. Polymorphisms of the BACH2 locus are associated with multiple autoimmune diseases including rheumatoid arthritis, lupus, diabetes, IBD, asthma, multiple sclerosis and other diseases. In related work, we found that BACH2 mutations underlie a previously unrecognized Mendelian monogenic primary immunodeficiency manifested by immunodeficiency and autoimmunity. Innate lymphoid cells (ILCs) represent a subset of cells that play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4 T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We found that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naive CD4 T cells during Th cell differentiation during parasite infection. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways. During this year, we have investigated the role of STAT5 in ILCs and the relationship between ILC poised epigenomes and acute activation in terms of rapid regulation of gene expression. In related epigenomic work, we investigated the role of histone variants in regulation of transcription. 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The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct in various tissues, has not been fully ascertained. We used mouse models of paralog deficiency to demonstrate that they are not equivalent for CD4+ helper T cells. We found that STAT5B is dominant for both effector and regulatory responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output confirms that STAT5B has far greater impact but, surprisingly, the data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, relative abundance of STAT5 imposes functional specificity (or dominance) in the face of widespread structural homology. In related collaborative work, we found that the Stat5a/b locus is subject to additional lineage-specific transcriptional control. CRISPR/Cas9-mediated genome editing was used to delete these sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels and a concomitant reduction of STAT5-dependent gene expression. We have previously shown that STATs, especially STAT1 and STAT4, are important drivers of expression of a lineage defining transcription factor (LDTF) in T helper 1 (Th1) cells termed T-bet encoded by Tbx21). IFN-g, a member of a large family of anti-pathogenic and anti-tumor IFNs, acting through STAT1 induces T-bet, which in turn supports IFN-g production in a feed-forward manner. In a study published this year, we showed that a cell-intrinsic role of T-bet determines how T cells perceive their secreted product in the environment. In the absence of T-bet, IFN-g aberrantly induced a type I IFN transcriptomic program in T cells. Specifically, T-bet preferentially repressed genes and pathways ordinarily activated by type I IFNs to ensure that its transcriptional response did not evoke an aberrant amplification of type I IFN signaling circuitry, otherwise triggered by its own product. Thus, this work identified an unanticipated function of a well-known LDTF. In addition to promoting Th1 effector commitment and production of the signature cytokine IFN-g, T-bet acts as a repressor in differentiated Th1 cells to prevent aberrant autocrine type I IFN and downstream signaling. Blimp-1 (encoded by Prdm1) is an LDTF expressed in differentiated effector T cells that extinguishes the fate of T follicular helper cells and limits autoimmunity. We found unexpectedly that STAT3 and not STAT6 plays a critical role in regulating Blimp-1 in TH2 cells. Furthermore, we found that the cytokine interleukin-10 (IL-10) acted directly on TH2 cells and was necessary and sufficient to induce optimal Blimp-1 expression through STAT3. Moreover, we found that Blimp-1 and STAT3 amplified IL-10 production in TH2 cells, creating a strong autoregulatory loop that enhanced Blimp-1 expression. Increased Blimp-1 in T cells antagonized STAT5-regulated cell cycle and antiapoptotic genes to limit cell expansion. By contrast, we found a very distinct mode of regulation of Blimp-1 in Th17 cells compared to Th2 cells. Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of Th17 cells. We found that IL-23 induces Blimp-1 and peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome-wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORt, STAT-3, and p300 at the Il23r, Il17a/f, and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. An important transcription factor that antagonizes effector differentiation of T cells is Bach2. In collaboration, we extended our previous work on Bach2 in CD4 T cells to study its role on the differentiation state of CD8 T cells. We found that the BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 sites to Jun family signal-dependent transcription factors. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation, but in effector cells reduced expression enabling unrestrained induction of TCR-driven programs. Polymorphisms of the BACH2 locus are associated with multiple autoimmune diseases including rheumatoid arthritis, lupus, diabetes, IBD, asthma, multiple sclerosis and other diseases. In related work, we found that BACH2 mutations underlie a previously unrecognized Mendelian monogenic primary immunodeficiency manifested by immunodeficiency and autoimmunity. Innate lymphoid cells (ILCs) represent a subset of cells that play key roles in host defense, barrier integrity, and homeostasis and mirror adaptive CD4 T helper (Th) cell subtypes in both usage of effector molecules and transcription factors. To better understand the relationship between ILC subsets and their Th cell counterparts, we measured genome-wide chromatin accessibility. We found that chromatin in proximity to effector genes is selectively accessible in ILCs prior to high-level transcription upon activation. Accessibility of these regions is acquired in a stepwise manner during development and changes little after in vitro or in vivo activation. Conversely, dramatic chromatin remodeling occurs in naive CD4 T cells during Th cell differentiation during parasite infection. This alteration results in a substantial convergence of Th2 cells toward ILC2 regulomes. Our data indicate extensive sharing of regulatory circuitry across the innate and adaptive compartments of the immune system, in spite of their divergent developing pathways. During this year, we have investigated the role of STAT5 in ILCs and the relationship between ILC poised epigenomes and acute activation in terms of rapid regulation of gene expression. In related epigenomic work, we investigated the role of histone variants in regulation of transcription. We found that mH2A1.2 is required for gene expression and cellular differentiation. Moreover, H3K27 acetylation was found to be dependent upon mH2A1.2, indicating a role for this factor in enhancer activation.
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    64 aberrant autocrine type I
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    78 antiapoptotic genes
    79 asthma
    80 asymmetric expression
    81 autoimmune diseases
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    83 autoimmunity
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    85 barrier integrity
    86 biological functions
    87 cell cycle
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    95 circuitry
    96 collaboration
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    104 cytokine loci Il2
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    131 environment
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    135 extent
    136 face
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    138 family
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    140 features
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    145 gene expression
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    147 genes
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    151 genomic distribution
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    155 histone variants
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    157 host defense
    158 immune system
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    183 mice
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    185 molecular basis
    186 mouse model
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    188 multiple sclerosis
    189 mutant animals
    190 naive CD4 T cells
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    193 optimal Blimp-1 expression
    194 other diseases
    195 overexpression studies
    196 own products
    197 paralog deficiency
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    199 parasite infection
    200 pathogenesis
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    202 pathway
    203 peripheral deletion
    204 previous work
    205 pro-inflammatory cytokines
    206 production
    207 program
    208 protective immunity
    209 proximity
    210 psoriasis
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    212 receptors
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    214 reduction
    215 region
    216 regulation
    217 regulatory circuitry
    218 regulatory responses
    219 related collaborative work
    220 related epigenomic work
    221 related work
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    223 relative abundance
    224 repressor
    225 rheumatoid arthritis
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    227 secreted product
    228 signature cytokine IFN
    229 sites
    230 spite
    231 stepwise manner
    232 strong autoregulatory loop
    233 study
    234 subset
    235 substantial convergence
    236 successful new strategy
    237 terminal differentiation
    238 terms
    239 transcription
    240 transcription factor STAT5
    241 transcription factors
    242 transcription factors RORt
    243 transcriptional response
    244 transcriptomic output
    245 transcriptomic program
    246 turn
    247 type I
    248 unanticipated function
    249 unrecognized Mendelian monogenic primary immunodeficiency
    250 unrestrained induction
    251 usage
    252 various tissues
    253 viral infection
    254 vitro
    255 vivo activation
    256 widespread structural homology
    257 work
    258 years
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