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Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation.

Li Q, Zou J, Wang M, Ding X, Chepelev I, Zhou X, Zhao W, Wei G, Cui J, Zhao K, Wang HY, Wang RF - Nat Commun (2014)

Bottom Line: The skewing of T-cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines.H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors.Our results identify Jmjd3 as an epigenetic factor in T-cell differentiation via changes in histone methylation and target gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas 77030, USA.

ABSTRACT
Epigenetic factors have been implicated in the regulation of CD4(+) T-cell differentiation. Jmjd3 plays a role in many biological processes, but its in vivo function in T-cell differentiation remains unknown. Here we report that Jmjd3 ablation promotes CD4(+) T-cell differentiation into Th2 and Th17 cells in the small intestine and colon, and inhibits T-cell differentiation into Th1 cells under different cytokine-polarizing conditions and in a Th1-dependent colitis model. Jmjd3 deficiency also restrains the plasticity of the conversion of Th2, Th17 or Treg cells to Th1 cells. The skewing of T-cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines. H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors. Our results identify Jmjd3 as an epigenetic factor in T-cell differentiation via changes in histone methylation and target gene expression.

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Jmjd3 ablation increases Th2, Th17, and Treg cell stability in vitro(a) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th1-inducing conditions for 3 days, and then exposed to Th2, Th17 or Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, Il-4, IL-17 and Foxp3-producing CD4+ T cells. (b) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th2 condition for 3 days, and then exposed to Th1, Th17 or Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, IL-4, IL-17 and Foxp3-producing CD4+ T cells. (c) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th17 condition for 3 days, and then exposed to Th1, Th2 and Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, IL-4, IL-17 and Foxp3-producing CD4+ T cells. (d) Naïve CD4+ T cells derived from WT and Jmjd3 cKO Foxp3-GFP reporter mice were differentiated under Treg conditions for 4 days. GFP+ cells were sorted and cultured under Th1, Th2 or Th17-inducing conditions for 2 days. Frequency of Foxp3-GFP+, IL-4, IL-17 and IFN-γ-producing CD4+ T cells. (e) WT and Jmjd3 cKO mice were i.v. injected with anti-CD3 to induce in vivo Th17 differentiation. Frequency of IL-17 and IFN-γ-producing CD4+ T cells from lymphocytes isolated from the small intestine, day 5 and day 8 after injection. (representative of three independent experiments, *p < 0.05 determined by Student's t-test).
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Figure 4: Jmjd3 ablation increases Th2, Th17, and Treg cell stability in vitro(a) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th1-inducing conditions for 3 days, and then exposed to Th2, Th17 or Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, Il-4, IL-17 and Foxp3-producing CD4+ T cells. (b) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th2 condition for 3 days, and then exposed to Th1, Th17 or Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, IL-4, IL-17 and Foxp3-producing CD4+ T cells. (c) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th17 condition for 3 days, and then exposed to Th1, Th2 and Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, IL-4, IL-17 and Foxp3-producing CD4+ T cells. (d) Naïve CD4+ T cells derived from WT and Jmjd3 cKO Foxp3-GFP reporter mice were differentiated under Treg conditions for 4 days. GFP+ cells were sorted and cultured under Th1, Th2 or Th17-inducing conditions for 2 days. Frequency of Foxp3-GFP+, IL-4, IL-17 and IFN-γ-producing CD4+ T cells. (e) WT and Jmjd3 cKO mice were i.v. injected with anti-CD3 to induce in vivo Th17 differentiation. Frequency of IL-17 and IFN-γ-producing CD4+ T cells from lymphocytes isolated from the small intestine, day 5 and day 8 after injection. (representative of three independent experiments, *p < 0.05 determined by Student's t-test).

Mentions: CD4+ T cells show remarkable plasticity and can differentiate into multiple T cell lineages depending on the local cytokine milieu2. To determine effects of Jmjd3 deficiency on T cell plasticity, CD4+ Th1 cells were generated from naïve WT and Jmjd3-deficient T cells under Th1 conditions with subsequent exposure to Th2, Th17, or Treg-inducing conditions. Compared with Jmjd3-deficient Th1 cells, a lower percentage of WT Th1 cells were converted into IL-4-producing Th2 T cells, including IL-4-only-producing (2.6% vs. 10.7%) and IL-4/IFN-γ double-producing (3.6% vs. 10.0%) T cells (Fig. 4a). Similarly, a lower percentage of WT Th1 cells converted into IL-17-producing Th17 T cells, but a similar percentage of WT Th1 cells converted into Treg cells, compared with Jmjd3-deficient cells (Fig. 4a).


Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation.

Li Q, Zou J, Wang M, Ding X, Chepelev I, Zhou X, Zhao W, Wei G, Cui J, Zhao K, Wang HY, Wang RF - Nat Commun (2014)

Jmjd3 ablation increases Th2, Th17, and Treg cell stability in vitro(a) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th1-inducing conditions for 3 days, and then exposed to Th2, Th17 or Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, Il-4, IL-17 and Foxp3-producing CD4+ T cells. (b) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th2 condition for 3 days, and then exposed to Th1, Th17 or Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, IL-4, IL-17 and Foxp3-producing CD4+ T cells. (c) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th17 condition for 3 days, and then exposed to Th1, Th2 and Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, IL-4, IL-17 and Foxp3-producing CD4+ T cells. (d) Naïve CD4+ T cells derived from WT and Jmjd3 cKO Foxp3-GFP reporter mice were differentiated under Treg conditions for 4 days. GFP+ cells were sorted and cultured under Th1, Th2 or Th17-inducing conditions for 2 days. Frequency of Foxp3-GFP+, IL-4, IL-17 and IFN-γ-producing CD4+ T cells. (e) WT and Jmjd3 cKO mice were i.v. injected with anti-CD3 to induce in vivo Th17 differentiation. Frequency of IL-17 and IFN-γ-producing CD4+ T cells from lymphocytes isolated from the small intestine, day 5 and day 8 after injection. (representative of three independent experiments, *p < 0.05 determined by Student's t-test).
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Related In: Results  -  Collection

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Figure 4: Jmjd3 ablation increases Th2, Th17, and Treg cell stability in vitro(a) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th1-inducing conditions for 3 days, and then exposed to Th2, Th17 or Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, Il-4, IL-17 and Foxp3-producing CD4+ T cells. (b) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th2 condition for 3 days, and then exposed to Th1, Th17 or Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, IL-4, IL-17 and Foxp3-producing CD4+ T cells. (c) WT and Jmjd3 cKO naïve CD4+ T cells were differentiated under Th17 condition for 3 days, and then exposed to Th1, Th2 and Treg-inducing cell culture conditions for 3 days. Frequency of IFN-γ, IL-4, IL-17 and Foxp3-producing CD4+ T cells. (d) Naïve CD4+ T cells derived from WT and Jmjd3 cKO Foxp3-GFP reporter mice were differentiated under Treg conditions for 4 days. GFP+ cells were sorted and cultured under Th1, Th2 or Th17-inducing conditions for 2 days. Frequency of Foxp3-GFP+, IL-4, IL-17 and IFN-γ-producing CD4+ T cells. (e) WT and Jmjd3 cKO mice were i.v. injected with anti-CD3 to induce in vivo Th17 differentiation. Frequency of IL-17 and IFN-γ-producing CD4+ T cells from lymphocytes isolated from the small intestine, day 5 and day 8 after injection. (representative of three independent experiments, *p < 0.05 determined by Student's t-test).
Mentions: CD4+ T cells show remarkable plasticity and can differentiate into multiple T cell lineages depending on the local cytokine milieu2. To determine effects of Jmjd3 deficiency on T cell plasticity, CD4+ Th1 cells were generated from naïve WT and Jmjd3-deficient T cells under Th1 conditions with subsequent exposure to Th2, Th17, or Treg-inducing conditions. Compared with Jmjd3-deficient Th1 cells, a lower percentage of WT Th1 cells were converted into IL-4-producing Th2 T cells, including IL-4-only-producing (2.6% vs. 10.7%) and IL-4/IFN-γ double-producing (3.6% vs. 10.0%) T cells (Fig. 4a). Similarly, a lower percentage of WT Th1 cells converted into IL-17-producing Th17 T cells, but a similar percentage of WT Th1 cells converted into Treg cells, compared with Jmjd3-deficient cells (Fig. 4a).

Bottom Line: The skewing of T-cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines.H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors.Our results identify Jmjd3 as an epigenetic factor in T-cell differentiation via changes in histone methylation and target gene expression.

View Article: PubMed Central - PubMed

Affiliation: Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas 77030, USA.

ABSTRACT
Epigenetic factors have been implicated in the regulation of CD4(+) T-cell differentiation. Jmjd3 plays a role in many biological processes, but its in vivo function in T-cell differentiation remains unknown. Here we report that Jmjd3 ablation promotes CD4(+) T-cell differentiation into Th2 and Th17 cells in the small intestine and colon, and inhibits T-cell differentiation into Th1 cells under different cytokine-polarizing conditions and in a Th1-dependent colitis model. Jmjd3 deficiency also restrains the plasticity of the conversion of Th2, Th17 or Treg cells to Th1 cells. The skewing of T-cell differentiation is concomitant with changes in the expression of key transcription factors and cytokines. H3K27me3 and H3K4me3 levels in Jmjd3-deficient cells are correlated with altered gene expression through interactions with specific transcription factors. Our results identify Jmjd3 as an epigenetic factor in T-cell differentiation via changes in histone methylation and target gene expression.

Show MeSH
Related in: MedlinePlus