The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage

Shan, Qiang; Zeng, Zhouhao; Xing, Shaojun; Li, Fengyin; Hartwig, Stacey M.; Gullicksrud, Jodi A.; Kurup, Samarchith P.; Braeckel-Budimir, Natalija Van; Yao, Su; Martin, Matthew D.; Varga, Steven M.; Taniuchi, Ichiro; Harty, John T.; Peng, Weiqun; Badovinac, Vladimir P.; Xue, Hai-Hui

doi:10.1038/ni.3773

Cited by 120 publications

(146 citation statements)

References 54 publications

(84 reference statements)

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“…This finding corroborates a previous study showing that changes in chromatin accessibility and transcription did not always match as Tregs adapted to different tissues 39 . Nevertheless, our identification of a pre-IEL signature, marked by the loss of key features of conventional CD4 and/or Treg programs, suggests that during tissue adaptation a cell must first shut down transcriptional programs in place (or decouple TFs bound to its DNA targets) that may prevent tissue imprinting, suggestion corroborated by previous studies describing roles of Runx3 to the CD8-lineage or tissue-resident memory T cells (TRM) 26,27 . A recent study also describes a stepwise process taken by Tregs, in which peripheral precursors gradually acquire chromatin accessibility and reprograming towards nonlymphoid-tissue Tregs.…”

Section: Discussionsupporting

confidence: 78%

“…Accessible chromatin regions with the RUNX binding motif increased during the iTreg to IEL progression, reaching peak significance in clusters 5 and 6. ThPOK downmodulation may leave space for other TF to bind in adjacent DNA regions, a possibility analogous to previously described roles of Runx3 to the CD8-lineage 26,27 . For instance, Runx3 can bind to ThPOK silencer regions that in turn allows for the expression of a CD8 program in thymocytes 28 .…”

Section: Thpok Downmodulation Together With the Epithelial Environmensupporting

confidence: 55%

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Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

London

Bilate

Castro

et al. 2020

Preprint

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Mesenteric lymph node (mLN) T cells undergo tissue adaptation upon migrating to intestinallamina propria (LP) and intraepithelial (IE) compartments, ensuring appropriate balance between tolerance and resistance. By combining mouse genetics with single-cell and chromatin analyses, we addressed the molecular imprinting of gut epithelium on T cells. Transcriptionally, conventional and regulatory (Treg) CD4 + T cells from mLN, LP and IE segregate based on the gut layer they occupy; trajectory analysis suggests a stepwise loss of CD4-programming and acquisition of an intraepithelial profile. Treg fate-mapping coupled with RNA-and ATAC-sequencing revealed that the Treg program shuts down before an intraepithelial program becomes fully accessible at the epithelium. Ablation of CD4 lineage-defining transcription factor ThPOK results in premature acquisition of an IEL profile by mLN Tregs, partially recapitulating epithelium imprinting. Thus, coordinated replacement of circulating lymphocyte program with site-specific transcriptional and chromatin changes is necessary for tissue imprinting.conversion include co-expression of CD4 and the CD8aa homodimer which is induced by a switch from conventional CD4-to-CD8 lineage-defining transcription factors. CD4-IELs downregulate ThPOK (encoded by Zbtb7b), expressed by all conventional mature CD4 + T cells and upregulate the long form of Runx3, expressed by mature CD8 + T cells 9,12,16 . While environmental cues and transcription factors involved in the differentiation of naïve CD4 + T cells into gut-adapted T cell subsets have been described in the past decade, the transcriptional and chromatin changes that accompany such tissue-specific imprinting have not been elucidated.We used genetic fate-mapping and gene ablation mouse models coupled with single-cell RNA-, ATACand ChIP-sequencing approaches to uncover the molecular mechanisms of how the intestinal tissue can imprint T-cell fate decisions on migrating mLN CD4 + T cells. We found that gut-associated CD4 + T cell transcriptional profiles largely segregate by tissue location, indicating that upon leaving the gut-draining LNs, migrating cells quickly adapt to either LP or IE compartments; IE-adapted cells followed a stepwise acquisition of an IEL profile through a distinct pre-IEL stage. We specifically followed how the generally stable Treg phenotype is destabilized upon T cell migration to the IE compartment. We found that the Treg program is first downregulated at a pre-IEL stage before a cytotoxic IEL program is made accessible at the chromatin levels and then subsequently transcribed. Finally, we showed that while natural ThPOK downmodulation marks the pre-IEL stage, premature ThPOK loss in Tregs allows for the expression of the IEL profile before the Treg program is fully shut down. Our studies uncovered wide, tissue-specific and stepwise chromatin and transcriptional changes in T cells upon transitioning from tissue-draining LNs to tissue sites and revealed specific roles for lineage-defining transcription factors in drivi...

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Section: Discussionsupporting

confidence: 78%

Section: Thpok Downmodulation Together With the Epithelial Environmensupporting

confidence: 55%

Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

London

Bilate

Castro

et al. 2020

Preprint

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“…In addition to the HLA region, variants in the ERAP1/2 loci (which encode enzymes required for HLA class I peptide trimming [43][44][45], and the RUNX3 locus, which encodes runt-related transcription factor 3, a transcription factor essential for CD8+ T cell development and differentiation [46][47][48] , are associated with AS and PsA as well as psoriasis [49][50][51][52] . The location of susceptibility variants associated with PsA has been shown to overlap with epigenetic marks of transcription (histone H3 lysine 4 trimethylation (H3K4me3), a histone modification and epigenetic marker of active promoters) in memory CD8+ T cells 52 ; in AS, susceptibility variants overlap with H3K4me3 marks across a range of immune cell types, including CD4+ and CD8+ T cells 53 .…”

Section: Genetics Of Spa With a Focus On The Mhc Class I Pathway And mentioning

confidence: 99%

IL-17 in the immunopathogenesis of spondyloarthritis

et al. 2018

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Spondyloarthritis (SpA) is a term that refers to a group of inflammatory diseases that includes psoriatic arthritis, axial SpA and nonradiographic axial SpA, reactive arthritis, enteropathic arthritis and undifferentiated SpA. The disease subtypes share clinical and immunological features, including joint inflammation (peripheral and axial skeleton); skin, gut and eye manifestations; and the absence of diagnostic autoantibodies (seronegative). The diseases also share genetic factors. The aetiology of SpA is still the subject of research by many groups worldwide. Evidence from genetic, experimental and clinical studies has accumulated to indicate a clear role for the IL-17 pathway in the pathogenesis of SpA. The IL-17 family consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F, of which IL-17A is the best studied. IL-17A is a pro-inflammatory cytokine that also has the capacity to promote angiogenesis and osteoclastogenesis. Of the six family members, IL-17A has the strongest homology with IL-17F. In this Review, we discuss how IL-17A and IL-17F and their cellular sources might contribute to the immunopathology of SpA.

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“…157,158 In addition, Runx3 deploys epigenetic marks (i.e., H3K27me3) to guard the fate of effector CD8 + T cells and prevent the expression of follicular helper T cell-related genes. 159 As to be discussed in the next section, a small population of CD4 + T cells acquire the expression of Runx3 and differentiate into CD8αα + CD4 + T RM cells in the gut IEL compartment. 160,161 More recently, using computational and pooled in vivo RNAi screens, Runx3 is reported to be a critical regulator in the establishment of T RM cell populations in both non-barrier tissues (salivary gland and kidney) and barrier tissues (IEL, skin and lung parenchyma) even though the expression of Runx3 is not specifically induced in T RM cells.…”

Section: Transcriptional Regulation Of Trm Cellsmentioning

confidence: 99%

Tissue-Specific Control of Tissue-Resident Memory T Cells

Liu

Zhang

2018

Crit Rev Immunol

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Tissue-resident memory T (TRM) cells have emerged to be a major component of T cell biology. Recent investigations have greatly advanced our understanding of TRMs. Common features have been discovered to distinguish memory T cells residing in various mucosal and non-mucosal tissues from their circulating counterparts. Given that most organs and tissues contain unique microenvironment, local signal-induced tissue-specific features are tightly associated with the differentiation, homeostasis and protective functions of TRMs. We will discuss the recent advances in TRM field with a special emphasis on the interaction between local signals and TRM cells in the context of individual tissue environment.

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The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage

Cited by 120 publications

References 54 publications

Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

Stepwise chromatin and transcriptional acquisition of an intraepithelial lymphocyte program

IL-17 in the immunopathogenesis of spondyloarthritis

Tissue-Specific Control of Tissue-Resident Memory T Cells

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