Genome-wide Analysis of STAT3-Mediated Transcription during Early Human Th17 Cell Differentiation

Tripathi, Subhash; Chen, Zhi; Larjo, Antti; Kanduri, Kartiek; Nousiainen, Kari; Äijö, Tarmo; Ricaño-Ponce, Isis; Hrdličková, Barbara; Tuomela, Soile; Laajala, Essi; Salo, Verna; Kumar, Vinod; Wijmenga, Cisca; Lähdesmäki, Harri; Lahesmaa, Riitta

doi:10.1016/j.celrep.2017.05.013

Cited by 97 publications

(118 citation statements)

References 43 publications

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“…49,50 STAT3 is a signaling molecule that regulates both T cell migration and Th17 differentiation. 51 These observations agree with our data showing that KCs initiate Th17 differentiation of naive T cells independent of the interaction between CD58 and CD2. Furthermore, the CD54/LFA-1-mediated phosphorylation of STAT3 fits our observation that STAT3 phosphorylation is still upregulated in naive T cells cultured with IFNγ-pretreated KCs in the absence of CD58/CD2-mediated costimulation.…”

Section: Discussionsupporting

confidence: 92%

Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin

et al. 2019

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The interplay between keratinocytes and immune cells, especially T cells, plays an important role in the pathogenesis of chronic inflammatory skin diseases. During psoriasis, keratinocytes attract T cells by releasing chemokines, while skin-infiltrating selfreactive T cells secrete proinflammatory cytokines, e.g., IFNγ and IL-17A, that cause epidermal hyperplasia. Similarly, in chronic graftversus-host disease, allogenic IFNγ-producing Th1/Tc1 and IL-17-producing Th17/Tc17 cells are recruited by keratinocyte-derived chemokines and accumulate in the skin. However, whether keratinocytes act as nonprofessional antigen-presenting cells to directly activate naive human T cells in the epidermis remains unknown. Here, we demonstrate that under proinflammatory conditions, primary human keratinocytes indeed activate naive human T cells. This activation required cell contact and costimulatory signaling via CD58/CD2 and CD54/LFA-1. Naive T cells costimulated by keratinocytes selectively differentiated into Th1 and Th17 cells. In particular, keratinocyte-initiated Th1 differentiation was dependent on costimulation through CD58/CD2. The latter molecule initiated STAT1 signaling and IFNγ production in T cells. Costimulation of T cells by keratinocytes resulting in Th1 and Th17 differentiation represents a new explanation for the local enrichment of Th1 and Th17 cells in the skin of patients with a chronic inflammatory skin disease. Consequently, local interference with T cell-keratinocyte interactions may represent a novel strategy for the treatment of Th1 and Th17 cell-driven skin diseases.In addition, in chronic graft-versus-host disease (GVHD), a major complication of allogenic stem cell transplantation, the KCmediated secretion of chemokines (CXCL9 and CXCL10) leads to the recruitment of alloreactive T cells into the skin. 14 These allogenic T cells predominantly belong to the IFNγ-producing Th1/ Tc1 and IL-17-producing Th17/Tc17 subpopulations and cause cutaneous manifestations, e.g., follicular erythema. [15][16][17] Although the pivotal role of KCs in non-contact-mediated communication during chronic skin inflammation is quite well understood, the direct interaction between KCs and T cells remains elusive. In particular, the potential of KCs to act as nonprofessional APCs, enabling them to costimulate T cells directly in the skin, is still debated.T cells require two distinct signals for activation and clonal expansion. The first signal is transmitted by the antigen-specific T cell receptor (TCR) on T cells, following recognition of antigenic peptides loaded on MHC class I or class II molecules expressed by APCs. The first signal secures the antigen specificity of the immune reaction. The second signal is transmitted through costimulatory receptors, dictating the progression to T cell activation. Between

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Section: Discussionsupporting

confidence: 92%

Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin

et al. 2019

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“…Both pY‐STAT3 levels and binding of STAT3 to the promoter region of PDK4 were highest in IL‐6‐stimulated Ctrl cells and reduced in the shSTAT3#456 and shSTAT3#843 cells compared to Ctrl (Appendix Fig S6C and D, Fig C). Known STAT3 targets Leucine Zipper ATF‐Like Transcription Factor (BATF) and JunB Proto‐Oncogene, AP‐1 Transcription Factor Subunit (JUNB) (Tripathi et al , ) were used as a positive control (Appendix Fig S6E and F, Table EV6). Immunoglobulin G (IgG) was used as a negative control.…”

Section: Resultsmentioning

confidence: 99%

“…Primer sequences used for ChIP are listed in Table . Known STAT3 binding sites in BATF and JUNB promoters described in Tripathi et al () were chosen as positive controls and confirmed by extraction of corresponding peaks from ENCODE STAT3 ChIP‐Seq HeLa‐S3 data (ENCSR000EDC) with UCSC Genome Browser ( http://genome.ucsc.edu). For the generation of PDK4 primer pairs, a STAT3 binding site in the promoter region of PDK4 detected by ENCODE STAT3 ChIP‐Seq HeLa‐S3 was extracted (see Appendix Supplementary Methods).…”

Section: Methodsmentioning

confidence: 99%

STAT3‐dependent analysis revealsPDK4as independent predictor of recurrence in prostate cancer

Oberhuber

Pecoraro

Rusz

et al. 2020

Molecular Systems Biology

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Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by utilizing a gene co-expression network of transcriptomics data in addition to laser-microdissected proteomics from human and murine prostate FFPE samples. We show up-regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up-regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis.

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“…We explored the STAT3/STAT6 binding sites using transcription factor binding site prediction software JASPAR 37 as well as existing ChIP-seq data across different cell lines. [38][39][40] We validated multiple sites (Suppl . Table S7) for (A-C) Macrophages were treated for 1h with IL-4 and IL-6 alone or in combination for (A) STAT3 ChIP, (B) STAT6 ChIP and 6h for (C) H3K9ac ChIP for indicated genes (n ≥ 4-6).…”

Section: Analysis Of Human Macrophage Transcriptome Changes In Responmentioning

confidence: 99%

IL-6 augments IL-4-induced polarization of primary human macrophages through synergy of STAT3, STAT6 and BATF transcription factors

et al. 2018

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Macrophages in the tumor microenvironment respond to complex cytokine signals. How these responses shape the phenotype of tumor-associated macrophages (TAMs) is incompletely understood. Here we explored how cytokines of the tumor milieu, interleukin (IL)-6 and IL-4, interact to influence target gene expression in primary human monocyte-derived macrophages (hMDMs). We show that dual stimulation with IL-4 and IL-6 synergistically modified gene expression. Among the synergistically induced genes are several targets with known pro-tumorigenic properties, such as CC-chemokine ligand 18 (CCL18), transforming growth factor alpha (TGFA) or CD274 (programmed cell death 1 ligand 1 (PD-L1)). We found that transcription factors of the signal transducer and activator of transcription (STAT) family, STAT3 and STAT6 bind regulatory regions of synergistically induced genes in close vicinity. STAT3 and STAT6 co-binding further induces the basic leucine zipper ATF-like transcription factor (BATF), which participates in synergistic induction of target gene expression. Functional analyses revealed increased MCF-7 and MDA-MB 231 tumor cell motility in response to conditioned media from co-treated hMDMs compared to cells incubated with media from single cytokine-treated hMDMs. Flow cytometric analysis of T cell populations upon co-culture with hMDMs polarized by different cytokines indicated that dual stimulation promoted immunosuppressive properties of hMDMs in a PD-L1-dependent manner. Analysis of clinical data revealed increased expression of BATF together with TAM markers in tumor stroma of breast cancer patients as compared to normal breast tissue stroma. Collectively, our findings suggest that IL-4 and IL-6 cooperate to alter the human macrophage transcriptome, endowing hMDMs with protumorigenic properties. ARTICLE HISTORY

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Genome-wide Analysis of STAT3-Mediated Transcription during Early Human Th17 Cell Differentiation

Cited by 97 publications

References 43 publications

Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin

Keratinocytes costimulate naive human T cells via CD2: a potential target to prevent the development of proinflammatory Th1 cells in the skin

STAT3‐dependent analysis revealsPDK4as independent predictor of recurrence in prostate cancer

IL-6 augments IL-4-induced polarization of primary human macrophages through synergy of STAT3, STAT6 and BATF transcription factors

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