The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells during Infection and Inflammation

Scheer, Sebastian; Runting, Jessica; Bramhall, Michael; Russ, Brendan E.; Zaini, Aidil; Ellemor, Jessie; Rodrigues, Grace; Ng, Judy; Zaph, Colby

doi:10.1016/j.celrep.2020.108505

Cited by 26 publications

(22 citation statements)

References 56 publications

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“…Previous studies demonstrated that Schistosoma haematobium and Ascaris lumbricoides infections induce changes in host DNA methylation and immune phenotypic changes in CD4 + T cells that hamper both IFN‐γ production and the downstream intracellular IFN‐γ signalling pathway [57]. Similarly, mice with a T‐cell‐specific deletion of the lysine methyltransferase DOTL1 failed to develop a Th2 cell response and were susceptible to infection with Trichuris muris [58]. On the other hand, epigenetic mechanisms can also modulate Treg cell responses.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis

Correale¹,

Marrodán²,

Contentti

2021

Immunology

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Multiple sclerosis (MS) is currently thought to arise by interactions between genetic susceptibility and environmental factors. Infections in general trigger autoimmune responses causing clinical manifestations of disease. However, as a result of regulatory T (Treg)‐ and regulatory B (Breg)‐cell induction, helminth infections tend to dampen disease activity. IL‐35, the newest member of the IL‐12 family, is an inhibitory cytokine composed of an EBI3β chain subunit, and an IL‐12p35 subunit. The aim of this study was to investigate the role of IL‐35 during parasite infections occurring in individuals with MS. Numbers of IL‐35‐producing Breg cells are higher in CSF from helminth‐infected than from uninfected MS subjects, a finding associated with decreased MRI disease activity. Interestingly, stimulation of CD19+ B cells with IL‐35 promotes conversion of these cells to Breg cells producing both IL‐35 and IL‐10. Coculture of B cells from helminth‐infected MS patients inhibits proliferation of Th1 and Th17 myelin peptide‐specific T cells, as well as production of IFN‐γ and IL‐17. Following activation, CD4+CD25+ Treg cells significantly upregulate expression of EBI3 and IL‐12p35 mRNA. Furthermore, CD4+CD25− T cells activated in the presence of IL‐35 induce a population of cells with regulatory function, known as iTR35. Finally, B cells from normal individuals cultured in vitro in the presence of the helminth antigen SEA increase expression of the transcription BATF, IRF4 and IRF8, acquiring a pattern similar to that of IL‐35 Breg cells. These data highlight the important immunoregulatory effects of IL‐35 on both Breg and Treg cells, observed in helminth‐infected MS subjects.

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Section: Discussionmentioning

confidence: 99%

Interleukin‐35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis

Correale¹,

Marrodán²,

Contentti

2021

Immunology

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“…DOT1L-mediated selective histone 3 lysine 79 (H3K79me2/3) modifications at the IL-6 and IFN-b1 promoters are required for the full activation of innate immune responses (28). DO1L plays an important role in regulating the differentiation and complete function of CD4+, CD8+T cells and B cells in the process of acquired immunity, while DO1L knockdown or mutation invalidates acquired immunity (29)(30)(31)(32). ZBTB1 (zinc finger and BTB domain containing 1) prevents DNA damage in replicating immune progenitors, allowing the generation of B cells, T cells, and myeloid cells (33).…”

Section: Discussionmentioning

confidence: 99%

The Prognostic Value of the DNA Repair Gene Signature in Head and Neck Squamous Cell Carcinoma

et al. 2021

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PurposeTo construct a prognostic signature composed of DNA repair genes to effectively predict the prognosis of patients with head and neck squamous cell carcinoma (HNSCC).MethodsAfter downloading the transcriptome and clinical data of HNSCC from the Cancer Genome Atlas (TCGA), 499 patients with HNSCC were equally divided into training and testing sets. In the training set, 13 DNA repair genes were screened using univariate proportional hazard (Cox) regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct a risk model, which was validated in the testing set.ResultsIn the training and testing sets, there were significant differences in the clinical outcomes of patients in the high- and low-risk groups showed by Kaplan-Meier survival curves (P < 0.001). Univariate and multivariate Cox regression analyses showed that the risk score had independent prognostic predictive ability (P < 0.001). At the same time, the immune cell infiltration, immune score, immune-related gene expression, and tumor mutation burden (TMB) of patients with HNSCC were also different between the high- and low-risk groups (P < 0.05). Finally, we screened several chemotherapeutics for HNSCC, which showed significant differences in drug sensitivity between the high- and low-risk groups (P < 0.05).ConclusionThis study constructed a 13-DNA-repair-gene signature for the prognosis of HNSCC, which could accurately and independently predict the clinical outcome of the patient. We then revealed the immune landscape, TMB, and sensitivity to chemotherapy drugs in different risk groups, which might be used to guide clinical treatment decisions.

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“…Another group recently used a T-cell-specific Dot1L-deficient infection mouse model and observed that the repressive effect of IFN-γ production by Dot1L was T-bet dependent. In this study, the enhanced IFN-γ secreting ability via Dot1L inhibition (with chemical probe SGC0946) in Th2 cells was abrogated by T-bet deletion ( 143 ). However, the opposite phenomenon was observed in GVHD setting.…”

Section: Epigenetic Programs and Pharmacological Modulations That Control Ifns In Allogeneic T Cells During Gvhdmentioning

confidence: 85%

The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations

2021

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. This beneficial effect is derived mainly from graft-versus-leukemia (GVL) effects mediated by alloreactive T cells. However, these alloreactive T cells can also induce graft-versus-host disease (GVHD), a life-threatening complication after allo-HSCT. Significant progress has been made in the dissociation of GVL effects from GVHD by modulating alloreactive T cell immunity. However, many factors may influence alloreactive T cell responses in the host undergoing allo-HSCT, including the interaction of alloreactive T cells with both donor and recipient hematopoietic cells and host non-hematopoietic tissues, cytokines, chemokines and inflammatory mediators. Interferons (IFNs), including type I IFNs and IFN-γ, primarily produced by monocytes, dendritic cells and T cells, play essential roles in regulating alloreactive T cell differentiation and function. Many studies have shown pleiotropic effects of IFNs on allogeneic T cell responses during GVH reaction. Epigenetic mechanisms, such as DNA methylation and histone modifications, are important to regulate IFNs’ production and function during GVHD. In this review, we discuss recent findings from preclinical models and clinical studies that characterize T cell responses regulated by IFNs and epigenetic mechanisms, and further discuss pharmacological approaches that modulate epigenetic effects in the setting of allo-HSCT.

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The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells during Infection and Inflammation

Cited by 26 publications

References 56 publications

Interleukin‐35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis

Interleukin‐35 is a critical regulator of immunity during helminth infections associated with multiple sclerosis

The Prognostic Value of the DNA Repair Gene Signature in Head and Neck Squamous Cell Carcinoma

The Effects of Interferons on Allogeneic T Cell Response in GVHD: The Multifaced Biology and Epigenetic Regulations

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