Dataset Information

HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4⁺CD8⁺ thymocytes for CD4-lineage commitment.

ABSTRACT: CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/?c/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.

SUBMITTER: Philips RL

PROVIDER: S-EPMC6338460 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4<sup>+</sup>CD8<sup>+</sup> thymocytes for CD4-lineage commitment.

Philips Rachael Laura RL Lee Jeong-Heon JH Gaonkar Krutika K Chanana Pritha P Chung Ji Young JY Romero Arocha Sinibaldo R SR Schwab Aaron A Ordog Tamas T Shapiro Virginia Smith VS

eLife 20190118

CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage ...[more]

PMID: 30657451

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Project description:BackgroundUrinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4+ T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-?, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4+ T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy.ResultsBlood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4+ lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4+ lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p?<?0.0001, IL13 -11 bp p?<?0.05, IL17A -122 bp p?<?0.01 and FOXP3 -77 bp p?>?0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4+ T cells for all four investigated loci, most prominently in IFNG p?<?0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4+ T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3.ConclusionIncreased lineage commitment in CD4+ T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4+ T cell lineages as a useful readout for clinical staging.

Dataset Information

HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4⁺CD8⁺ thymocytes for CD4-lineage commitment.

Publications

HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4<sup>+</sup>CD8<sup>+</sup> thymocytes for CD4-lineage commitment.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4+CD8+ thymocytes for CD4-lineage commitment.

Publications

HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4<sup>+</sup>CD8<sup>+</sup> thymocytes for CD4-lineage commitment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4⁺CD8⁺ thymocytes for CD4-lineage commitment.