Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation

The dynamics of CD4 + T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4 + T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (T H 1) and follicular helper T (T FH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated T H 1 and T FH trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between T FH and central memory were revealed, with antimalarials modulating these responses and boosting T H 1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4 + T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations (http://haquelab.mdhs.unimelb.edu.au/cd4_memory/).

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“…37 ) and Satb1 (ref. 38 ). Our analysis suggested a continuum between T FH and GC T FH cells, with T CM cells as a separate, Fig.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome dynamics of CD4+ T cells during malaria maps gradual transit from effector to memory

et al. 2020

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“…Mice with conditional deletion of Satb1 in Th17 cells were resistant to the development of EAE. Interestingly, Satb1-deficient Th17 cells showed normal IL-17 but impaired GM-CSF production [190], a key cytokine for EAE progression [7,8]. IL-23 but not IL-6 or IL-1β induced Satb1 expression.…”

Section: Satb1mentioning

confidence: 96%

“…Recently, IL-23 was shown to induce the expression of the special AT-rich sequence-binding protein-1 (Satb1) [190] (Figure 4). Satb1 is a chromatin organizer with an essential role controlling the expression of a large number of genes that participate in T cell development and activation, and Satb1 directly recruits chromatin modifiers to the loci of its target genes [191].…”

Section: Satb1mentioning

confidence: 99%

“…Mechanistically, RNAseq analysis of wild type and Satb1-deficient Th17 cells extracted from the spinal cord after EAE induction showed that the expression of basic helix-loop-helix transcription factor Bhlhe40 was lost in Satb1-null cells [190]. The transcription factor Bhlhe40 is required for GM-CSF production and EAE induction [192,193], and the reconstitution of Bhlhe40 expression by retroviral transduction restored the pathogenic function of Sabt1-deficient Th17 [190]. Thus, the targeting of the Satb1/Bhlhe40 axis would be an interesting therapeutic opportunity, in particular for multiple sclerosis treatments.…”

Section: Satb1mentioning

confidence: 99%

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Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

Pastor-Fernández

Mariblanca

Navarro

2020

Cells

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The interleukin 23 (IL-23) is a key pro-inflammatory cytokine in the development of chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases, multiple sclerosis, or rheumatoid arthritis. The pathological consequences of excessive IL-23 signaling have been linked to its ability to promote the production of inflammatory mediators, such as IL-17, IL-22, granulocyte-macrophage colony-stimulating (GM-CSF), or the tumor necrosis factor (TNFα) by target populations, mainly Th17 and IL-17-secreting TCRγδ cells (Tγδ17). Due to their pivotal role in inflammatory diseases, IL-23 and its downstream effector molecules have emerged as attractive therapeutic targets, leading to the development of neutralizing antibodies against IL-23 and IL-17 that have shown efficacy in different inflammatory diseases. Despite the success of monoclonal antibodies, there are patients that show no response or partial response to these treatments. Thus, effective therapies for inflammatory diseases may require the combination of multiple immune-modulatory drugs to prevent disease progression and to improve quality of life. Alternative strategies aimed at inhibiting intracellular signaling cascades using small molecule inhibitors or interfering peptides have not been fully exploited in the context of IL-23-mediated diseases. In this review, we discuss the current knowledge about proximal signaling events triggered by IL-23 upon binding to its membrane receptor to bring to the spotlight new opportunities for therapeutic intervention in IL-23-mediated pathologies.

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“…This was partially explained by a deficiency in regulatory T cells [39,40]. Notably, other knockout animals deleting SATB1 downstream of the DP stage, namely Satb1 fl/fl Thpok-Cre + and Satb1 fl/fl Foxp3-Cre + , do not manifest autoimmunity and even the CD4SP and CD8SP cell populations do not display any major changes [39,41]. Collectively, these findings underpin the importance of SATB1 during the DP stage of T cell development, although the detailed molecular mechanisms of its mode of action are still missing.…”

Section: Introductionmentioning

confidence: 99%

SATB1-mediated chromatin landscape in T cells

Ζελένκα

Spilianakis

2020

Nucleus

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The regulatory circuits that define developmental decisions of thymocytes are still incompletely resolved. SATB1 protein is predominantly expressed at the CD4 + CD8 + cell stage exerting its broad transcription regulation potential with both activatory and repressive roles. A series of posttranslational modifications and the presence of potential SATB1 protein isoforms indicate the complexity of its regulatory potential. The most apparent mechanism of its involvement in gene expression regulation is via the orchestration of long-range chromatin loops between genes and their regulatory elements. Multiple SATB1 perturbations in mice uncovered a link to autoimmune diseases while clinical investigations on cancer research uncovered that SATB1 has a promoting role in several types of cancer and can be used as a prognostic biomarker. SATB1 is a multivalent tissue-specific factor with a broad and yet undetermined regulatory potential. Future investigations on this protein could further uncover T cell-specific regulatory pathways and link them to (patho)physiology.

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Satb1 regulates the effector program of encephalitogenic tissue Th17 cells in chronic inflammation

Cited by 29 publications

References 64 publications

Transcriptome dynamics of CD4+ T cells during malaria maps gradual transit from effector to memory

Transcriptome dynamics of CD4+ T cells during malaria maps gradual transit from effector to memory

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

SATB1-mediated chromatin landscape in T cells

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