Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

Sidwell, Tom; Liao, Yang; Garnham, Alexandra L.; Vasanthakumar, Ajithkumar; Gloury, Renee; Blume, Jonas; Teh, Peggy P; Chisanga, David; Thelemann, Christoph; Rivera, Fabian de Labastida; Engwerda, Christian; Corcoran, Lynn M.; Kometani, Kohei; Kurosaki, Tomohiro; Smyth, Gordon K.; Shi, Wei; Kallies, Axel

doi:10.1038/s41467-019-14112-2

Cited by 71 publications

(76 citation statements)

References 68 publications

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“…The perturbations in signalling molecules we see following activation of T cells from older donors and their increased expression of IRF4 led us to hypothesise that IRF4 may regulate RBPJ expression. Reanalysis of recently published RNA‐Seq data showed that Irf4 ‐deficient mouse CD4 + T cells had reduced levels of Rbpj gene expression following activation (Log2 FC = −0.89, p = 8.62 × 10 −5 ; (Sidwell et al, 2020). We re‐analysed the published ATAC‐Seq and ChIP‐Seq libraries from this work to look at the potential IRF4‐dependent regulation of Rbpj expression.…”

Section: Resultsmentioning

confidence: 99%

Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ

et al. 2021

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Ageing profoundly changes our immune system and is thought to be a driving factor in the morbidity and mortality associated with infectious disease in older people. We have previously shown that the impaired immunity to vaccination that occurs in aged individuals is partly attributed to the effect of age on T follicular helper (Tfh) cell formation. In this study, we examined how age intrinsically affects Tfh cell formation in both mice and humans. We show increased formation of Tfh precursors (pre‐Tfh) but no associated increase in germinal centre (GC)‐Tfh cells in aged mice, suggesting age‐driven promotion of only early Tfh cell differentiation. Mechanistically, we show that ageing alters TCR signalling which drives expression of the Notch‐associated transcription factor, RBPJ. Genetic or chemical modulation of RBPJ or Notch rescues this age‐associated early Tfh cell differentiation, and increased intrinsic Notch activity recapitulates this phenomenon in younger mice. Our data offer mechanistic insight into the age‐induced changes in T‐cell activation that affects the differentiation and ultimately the function of effector T cells.

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Section: Resultsmentioning

confidence: 99%

Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ

et al. 2021

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“…Repression of IFN-γ expression is a critical biological function of BACH2 not only in conventional CD4 + Th1 cells and CD8 + T cells, but also during early iT reg cell development, where BACH2-mediated repression of IFN-γ is required for stabilization of iT reg differentiation prior to Foxp3 induction 11 – 13 . Moreover, we and others have shown that within lineage-committed Foxp3 + T reg cells, BACH2 is re-purposed and is not required to maintain Foxp3 expression or suppress IFN-γ expression, but rather blocks the TCR-driven transition between resting T reg (rT reg ) and activated T reg (aT reg ) states 20 , 21 . Given these observations, we chose to study the regulation of Ifng expression by BACH2 in the Foxp3-negative Jurkat cell line.…”

Section: Discussionmentioning

confidence: 97%

A cell-based bioluminescence assay reveals dose-dependent and contextual repression of AP-1-driven gene expression by BACH2

Vardaka

Lozano

Bot³

et al. 2020

Sci Rep

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Whereas effector CD4+ and CD8+ T cells promote immune activation and can drive clearance of infections and cancer, CD4+ regulatory T (Treg) cells suppress their function, contributing to both immune homeostasis and cancer immunosuppression. The transcription factor BACH2 functions as a pervasive regulator of T cell differentiation, promoting development of CD4+ Treg cells and suppressing the effector functions of multiple effector T cell (Teff) lineages. Here, we report the development of a stable cell-based bioluminescence assay of the transcription factor activity of BACH2. Tetracycline-inducible BACH2 expression resulted in suppression of phorbol 12-myristate 13-acetate (PMA)/ionomycin-driven activation of a luciferase reporter containing BACH2/AP-1 target sequences from the mouse Ifng + 18k enhancer. BACH2 expression repressed the luciferase signal in a dose-dependent manner but this activity was abolished at high levels of AP-1 signalling, suggesting contextual regulation of AP-1 driven gene expression by BACH2. Finally, using the reporter assay developed, we find that the histone deacetylase 3 (HDAC3)-selective inhibitor, RGFP966, inhibits BACH2-mediated repression of signal-driven luciferase expression. In addition to enabling mechanistic studies, this cell-based reporter may enable identification of small molecule agonists or antagonists of BACH2 function for drug development.

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“…5b,c). The CD4_Tfr cluster correlated with cognate stimulated CD4_Stim4.3 cluster with genes (IL18R1, FOXP1, BCL2, TRAF4) related to the activation and maintenance of Tregs [62][63][64][65] (Fig. 5d,l).…”

Section: Cd38 + Ptreg-infiltrates Correlate With Poor Clinical Outcommentioning

confidence: 92%

The functional and phenotypic diversity of single T-cell infiltrates in human colorectal cancer as correlated with clinical outcome

Masuda

Kornberg

Lin

et al. 2020

Preprint

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Although degree of T-cell infiltration in CRC was shown to correlate with a positive prognosis, the contribution of phenotypically and functionally distinct T cell subtypes within tumors remains unclear. We analyzed 37,931 single T cells with respect to transcriptome, TCR sequence and 23 cell surface proteins, from tumors and adjacent normal colon of 16 patients. Our comprehensive analysis revealed two phenotypically distinct cytotoxic T cell populations within tumors, including positively prognostic effector memory cells and non-prognostic resident memory cells. These cytotoxic T cell infiltrates transitioned from effector memory to resident memory in a stage-dependent manner. We further defined several Treg subpopulations within tumors. While Tregs overall were associated with positive clinical outcomes, CD38+ peripherally-derived Tregs, phenotypically related to Th17 cells, correlated with poor outcomes independent of cancer stage. Thus, our data highlight the diversity of T cells in CRC and demonstrate the prognostic significance of distinct T cell subtypes, which could inform therapeutic strategies.

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Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

Cited by 71 publications

References 68 publications

Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ

Ageing promotes early T follicular helper cell differentiation by modulating expression of RBPJ

A cell-based bioluminescence assay reveals dose-dependent and contextual repression of AP-1-driven gene expression by BACH2

The functional and phenotypic diversity of single T-cell infiltrates in human colorectal cancer as correlated with clinical outcome

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