KDM6B-dependent chromatin remodeling underpins effective virus-specific CD8+ T cell differentiation

Li, Jasmine; Hardy, Kristine; Olshansky, Moshe; Barugahare, Adele; Gearing, Linden J.; Sng, Xavier Y.X.; Nguyen, Michelle; Piovesan, Dana; Russ, Brendan E.; Gruta, Nicole L. La; Hertzog, Paul J.; Rao, Sudha; Turner, Stephen J.

doi:10.1016/j.celrep.2021.108839

Cited by 22 publications

(22 citation statements)

References 53 publications

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“…Using experimental methods we show that iron deprivation impairs chromatin remodelling in Th17 cells with elevated expression of the KDM6b target, H3K27me3. While we cannot be certain that the increase in H3K27me3 is due to reduced demethylation by KDM6A/B rather than increased methylation, previous studies have indicated that inhibition of KDM6A/B does impair Th17 differentiation and CD8+ T-cell proliferation and memory formation (39,46). In contrast, while DNA synthesis did not score amongst the highest enrichment terms in pathway analysis, two critical enzymes involved in DNA synthesis, RRM2 and DNA2, were amongst the most highly differentially regulated iron interacting proteins in activated T-cells, indicating that iron dependent DNA synthesis proteins are likely critical for T-cell activation.…”

Section: Discussionmentioning

confidence: 94%

Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation

et al. 2021

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Recent findings have shown that iron is a powerful regulator of immune responses, which is of broad importance because iron deficiency is highly prevalent worldwide. However, the underlying reasons of why iron is needed by lymphocytes remain unclear. Using a combination of mathematical modelling, bioinformatic analysis and experimental work, we studied how iron influences T-cells. We identified iron-interacting proteins in CD4+ and CD8+ T-cell proteomes that were differentially expressed during activation, suggesting that pathways enriched with such proteins, including histone demethylation, may be impaired by iron deficiency. Consistent with this, iron-starved Th17 cells showed elevated expression of the repressive histone mark H3K27me3 and displayed reduced RORγt and IL-17a, highlighting a previously unappreciated role for iron in T-cell differentiation. Quantitatively, we estimated T-cell iron content and calculated that T-cell iron demand rapidly and substantially increases after activation. We modelled that these increased requirements will not be met during clinically defined iron deficiency, indicating that normalizing serum iron may benefit adaptive immunity. Conversely, modelling predicted that excess serum iron would not enhance CD8+ T-cell responses, which we confirmed by immunising inducible hepcidin knock-out mice that have very high serum iron concentrations. Therefore, iron deficiency impairs multiple aspects of T-cell responses, while iron overload likely has milder effects.

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Section: Discussionmentioning

confidence: 94%

Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation

et al. 2021

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“…Transcriptional factors, including Tbx21 (also known as T-bet), Runx3 and Thpok, are involved in the regulation of intestinal IELs [ 33 , 35 ]. In conventional CD8 + T cells, the expression of Tbx21, which directs the CD8 + lineage-specific transcriptional program, is controlled by H3K27Me3 [ 24 , 41 ]. However, the expression of these transcriptional factors showed no alteration between two groups (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The JmjC catalytic domain-containing Kdm6 family proteins Kdm6a and Kdm6b are demethylases responsible for the demethylation of H3K27Me/2/3 [22]. Kdm6a negatively regulates the memory formation antigenspecific CD8 + T cells, and Kdm6b is essential for the differentiation of virus-specific CD8 + T cells and the generation of effector CD8 + T cells [23][24][25]. Kdm6b maintains Th17 cell differentiation and thymocyte egress by promoting the demethylation of H3K27Me3 at the Rorc, S1pr1 and Pdlim4 gene loci [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

The histone demethylase Kdm6b regulates the maturation and cytotoxicity of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes

Zhang

Liu

et al. 2022

Cell Death Differ

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Intestinal intraepithelial lymphocytes (IELs) are distributed along the length of the intestine and are considered the frontline of immune surveillance. The precise molecular mechanisms, especially epigenetic regulation, of their development and function are poorly understood. The trimethylation of histone 3 at lysine 27 (H3K27Me3) is a kind of histone modifications and associated with gene repression. Kdm6b is an epigenetic enzyme responsible for the demethylation of H3K27Me3 and thus promotes gene expression. Here we identified Kdm6b as an important intracellular regulator of small intestinal IELs. Mice genetically deficient for Kdm6b showed greatly reduced numbers of TCRαβ+CD8αα+ IELs. In the absence of Kdm6b, TCRαβ+CD8αα+ IELs exhibited increased apoptosis, disturbed maturation and a compromised capability to lyse target cells. Both IL-15 and Kdm6b-mediated demethylation of histone 3 at lysine 27 are responsible for the maturation of TCRαβ+CD8αα+ IELs through upregulating the expression of Gzmb and Fasl. In addition, Kdm6b also regulates the expression of the gut-homing molecule CCR9 by controlling H3K27Me3 level at its promoter. However, Kdm6b is dispensable for the reactivity of thymic precursors of TCRαβ+CD8αα+ IELs (IELPs) to IL-15 and TGF-β. In conclusion, we showed that Kdm6b plays critical roles in the maturation and cytotoxic function of small intestinal TCRαβ+CD8αα+ IELs.

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“…Aberrant nuclear membrane phenotypes have been associated with disease pathologies ( Muchir and Worman 2004 ; Fichtman et al, 2019 ). Examination of whole nuclei morphology with the detail from super-resolution imaging could enhanced visualization of previously uncharacterized structural changes brought about by virally-induced differentiation ( Li et al, 2021 ), genetic anomalies, or drug treatments ( Rozario et al, 2021 ). The nuclear lamina, as imaged in this work via lamin B1, also provides a distinct outline of the nucleus.…”

Section: Discussionmentioning

confidence: 99%

3D Single Molecule Super-Resolution Microscopy of Whole Nuclear Lamina

et al. 2022

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Single molecule (SM) super-resolution microscopies bypass the diffraction limit of conventional optical techniques and provide excellent spatial resolutions in the tens of nanometers without overly complex microscope hardware. SM imaging using optical astigmatism is an efficient strategy for visualizing subcellular features in 3D with a z-range of up to ∼1 µm per acquisition. This approach however, places high demands on fluorophore brightness and photoswitching resilience meaning that imaging entire cell volumes in 3D using SM super-resolution remains challenging. Here we employ SM astigmatism together with multiplane acquisition to visualize the whole nuclear lamina of COS-7 and T cells in 3D. Nuclear lamina provides structural support to the nuclear envelope and participates in vital nuclear functions including internuclear transport, chromatin organization and gene regulation. Its position at the periphery of the nucleus provides a visible reference of the nuclear boundary and can be used to quantify the spatial distribution of intranuclear components such as histone modifications and transcription factors. We found Alexa Fluor 647, a popular photoswitchable fluorophore, remained viable for over an hour of continuous high laser power exposure, and provided sufficient brightness detectable up to 8 µm deep into a cell, allowing us to capture the entire nuclear lamina in 3D. Our approach provides sufficient super-resolution detail of nuclear lamina morphology to enable quantification of overall nuclear dimensions and local membrane features.

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KDM6B-dependent chromatin remodeling underpins effective virus-specific CD8+ T cell differentiation

Cited by 22 publications

References 53 publications

Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation

Analysis of Iron and Iron-Interacting Protein Dynamics During T-Cell Activation

The histone demethylase Kdm6b regulates the maturation and cytotoxicity of TCRαβ+CD8αα+ intestinal intraepithelial lymphocytes

3D Single Molecule Super-Resolution Microscopy of Whole Nuclear Lamina

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