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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 promotes Th2 differentiation and suppresses Th1 differentiation in vivo(a) Naïve CD4+ T cells (CD4+CD25−CD62L+CD44low) from WT and Jmjd3 cKO mice were FACS-purified and i.p. injected into irradiated Rag2−/−γc−/− mice (2 × 106 cells/mouse). Body weight loss was monitored daily, indicating colitis progression (data are expressed as mean ± SD from three independent experiments, n = 5 mice in each group, *p < 0.05). (b) Percentages of splenic and colonic IL-4 and IFN-γ-producing CD4+ T cells from mice with colitis, one month following adoptive transfer of WT and Jmjd3 cKO naïve CD4+ T cells. Mean percentage of indicated T cell populations ± SD shown as histograms (right panel) (n = 3 mice per group, *p < 0.05). (c) WT and Jmjd3 cKO naïve CD4+ T cells (2 × 106) were i.v. injected into irradiated Rag2−/−γc−/− mice. Ten days later, frequency of IL-4 and IFN-γ-producing T cells from isolated splenocytes. Mean percentage of the indicated cell populations ± SD as shown by histograms (right panel) (representative results from at least three independent experiments, n = 3 per group, *p < 0.05). (d) Naïve CD4+ T cells and nTreg cells (CD4+CD25+) from WT and Jmjd3 cKO mice were FACS-purified and i.p. injected into Rag2−/−γc−/− mice (1 × 106 T cells + 0.2 × 106 nTreg cells per mouse). Body weight loss was monitored daily for colitis progression and reported as the mean ± SD from three independent experiments (n = 5 mice in each group,*p < 0.05). (e) Colitis score for individual Rag2−/−γc−/− mice (points) receiving indicated T cells and Treg cells (n = 5 mice in each group, *p < 0.05 determined by Student's t-test). (f) H&E staining of colon from Rag2−/−γc−/− mice receiving indicated T cells. Scale bar = 200 μm.
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Figure 3: Jmjd3 ablation promotes Th2 differentiation and suppresses Th1 differentiation in vivo(a) Naïve CD4+ T cells (CD4+CD25−CD62L+CD44low) from WT and Jmjd3 cKO mice were FACS-purified and i.p. injected into irradiated Rag2−/−γc−/− mice (2 × 106 cells/mouse). Body weight loss was monitored daily, indicating colitis progression (data are expressed as mean ± SD from three independent experiments, n = 5 mice in each group, *p < 0.05). (b) Percentages of splenic and colonic IL-4 and IFN-γ-producing CD4+ T cells from mice with colitis, one month following adoptive transfer of WT and Jmjd3 cKO naïve CD4+ T cells. Mean percentage of indicated T cell populations ± SD shown as histograms (right panel) (n = 3 mice per group, *p < 0.05). (c) WT and Jmjd3 cKO naïve CD4+ T cells (2 × 106) were i.v. injected into irradiated Rag2−/−γc−/− mice. Ten days later, frequency of IL-4 and IFN-γ-producing T cells from isolated splenocytes. Mean percentage of the indicated cell populations ± SD as shown by histograms (right panel) (representative results from at least three independent experiments, n = 3 per group, *p < 0.05). (d) Naïve CD4+ T cells and nTreg cells (CD4+CD25+) from WT and Jmjd3 cKO mice were FACS-purified and i.p. injected into Rag2−/−γc−/− mice (1 × 106 T cells + 0.2 × 106 nTreg cells per mouse). Body weight loss was monitored daily for colitis progression and reported as the mean ± SD from three independent experiments (n = 5 mice in each group,*p < 0.05). (e) Colitis score for individual Rag2−/−γc−/− mice (points) receiving indicated T cells and Treg cells (n = 5 mice in each group, *p < 0.05 determined by Student's t-test). (f) H&E staining of colon from Rag2−/−γc−/− mice receiving indicated T cells. Scale bar = 200 μm.

Mentions: Having established that Jmjd3 ablation alters CD4+ T cell differentiation in vitro, we next sought to validate these findings in vivo using a Th1-dependent colitis model. Intraperitoneal (i.p.) adoptive transfer of freshly isolated and purified naïve WT CD4+ T cells into lymphopenic Rag2−/−γc−/− mice caused spontaneous T cell activation and inflammatory colitis, leading to body weight loss (Fig. 3a). In contrast, Rag2−/−γc−/− mice receiving naïve CD4+ T cells from Jmjd3 cKO mice developed a milder colitis, with a body weight loss less than that of mice receiving WT T cells (Fig. 3a). FACS analysis of splenic and intestinal CD4+ T cells revealed a marked increase in IL-4-producing Th2 cells and a decrease in IFN-γ-producing Th1 cells in Rag2−/−γc−/− mice receiving Jmjd3-deficient T cells compared with those receiving WT CD4+ T cells (Fig. 3b). Consistently, IFN-γ-producing Th1 cells were decreased in Rag2−/−γc−/− mice receiving intravenous Jmjd3 cKO naïve CD4+ T cells compared with those receiving WT CD4+ T cells (Fig. 3c). To further determine the role of Jmjd3-deficient Th1 cells in the colitis models with or without Treg cells from WT and Jmjd3-deficient mice, we isolated and transferred WT or Jmjd3-deficient CD4+ T cells into lymphopenic Rag2−/−γc−/− mice, and measured percent initial body weight change. Consistent with our findings in Fig. 3a, Jmjd3-deficient T cells limited colitis in Rag2−/−γc−/− mice (Fig. 3d). To determine whether Jmjd3 deficiency affects Treg cell suppressive function in the Th1-mediated colitis model, we isolated and transferred WT and Jmjd3-deficient Treg cells together with naïve WT CD4+ T cells into lymphopenic Rag2−/−γc−/− mice. Co-transfer of both naïve CD4+ T cells and Treg cells suppressed weight loss and decreased colitis score at 40 days post-cell transfer regardless of whether the Treg cells were derived from WT or Jmjd3-deficient mice (Fig. 3d, 3e, 3f). Jmjd3 ablation inhibits Th1 differentiation and promotes Th2 differentiation in an in vivo colitis model, but does not affect the suppressive function of Treg cells.


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 promotes Th2 differentiation and suppresses Th1 differentiation in vivo(a) Naïve CD4+ T cells (CD4+CD25−CD62L+CD44low) from WT and Jmjd3 cKO mice were FACS-purified and i.p. injected into irradiated Rag2−/−γc−/− mice (2 × 106 cells/mouse). Body weight loss was monitored daily, indicating colitis progression (data are expressed as mean ± SD from three independent experiments, n = 5 mice in each group, *p < 0.05). (b) Percentages of splenic and colonic IL-4 and IFN-γ-producing CD4+ T cells from mice with colitis, one month following adoptive transfer of WT and Jmjd3 cKO naïve CD4+ T cells. Mean percentage of indicated T cell populations ± SD shown as histograms (right panel) (n = 3 mice per group, *p < 0.05). (c) WT and Jmjd3 cKO naïve CD4+ T cells (2 × 106) were i.v. injected into irradiated Rag2−/−γc−/− mice. Ten days later, frequency of IL-4 and IFN-γ-producing T cells from isolated splenocytes. Mean percentage of the indicated cell populations ± SD as shown by histograms (right panel) (representative results from at least three independent experiments, n = 3 per group, *p < 0.05). (d) Naïve CD4+ T cells and nTreg cells (CD4+CD25+) from WT and Jmjd3 cKO mice were FACS-purified and i.p. injected into Rag2−/−γc−/− mice (1 × 106 T cells + 0.2 × 106 nTreg cells per mouse). Body weight loss was monitored daily for colitis progression and reported as the mean ± SD from three independent experiments (n = 5 mice in each group,*p < 0.05). (e) Colitis score for individual Rag2−/−γc−/− mice (points) receiving indicated T cells and Treg cells (n = 5 mice in each group, *p < 0.05 determined by Student's t-test). (f) H&E staining of colon from Rag2−/−γc−/− mice receiving indicated T cells. Scale bar = 200 μm.
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Figure 3: Jmjd3 ablation promotes Th2 differentiation and suppresses Th1 differentiation in vivo(a) Naïve CD4+ T cells (CD4+CD25−CD62L+CD44low) from WT and Jmjd3 cKO mice were FACS-purified and i.p. injected into irradiated Rag2−/−γc−/− mice (2 × 106 cells/mouse). Body weight loss was monitored daily, indicating colitis progression (data are expressed as mean ± SD from three independent experiments, n = 5 mice in each group, *p < 0.05). (b) Percentages of splenic and colonic IL-4 and IFN-γ-producing CD4+ T cells from mice with colitis, one month following adoptive transfer of WT and Jmjd3 cKO naïve CD4+ T cells. Mean percentage of indicated T cell populations ± SD shown as histograms (right panel) (n = 3 mice per group, *p < 0.05). (c) WT and Jmjd3 cKO naïve CD4+ T cells (2 × 106) were i.v. injected into irradiated Rag2−/−γc−/− mice. Ten days later, frequency of IL-4 and IFN-γ-producing T cells from isolated splenocytes. Mean percentage of the indicated cell populations ± SD as shown by histograms (right panel) (representative results from at least three independent experiments, n = 3 per group, *p < 0.05). (d) Naïve CD4+ T cells and nTreg cells (CD4+CD25+) from WT and Jmjd3 cKO mice were FACS-purified and i.p. injected into Rag2−/−γc−/− mice (1 × 106 T cells + 0.2 × 106 nTreg cells per mouse). Body weight loss was monitored daily for colitis progression and reported as the mean ± SD from three independent experiments (n = 5 mice in each group,*p < 0.05). (e) Colitis score for individual Rag2−/−γc−/− mice (points) receiving indicated T cells and Treg cells (n = 5 mice in each group, *p < 0.05 determined by Student's t-test). (f) H&E staining of colon from Rag2−/−γc−/− mice receiving indicated T cells. Scale bar = 200 μm.
Mentions: Having established that Jmjd3 ablation alters CD4+ T cell differentiation in vitro, we next sought to validate these findings in vivo using a Th1-dependent colitis model. Intraperitoneal (i.p.) adoptive transfer of freshly isolated and purified naïve WT CD4+ T cells into lymphopenic Rag2−/−γc−/− mice caused spontaneous T cell activation and inflammatory colitis, leading to body weight loss (Fig. 3a). In contrast, Rag2−/−γc−/− mice receiving naïve CD4+ T cells from Jmjd3 cKO mice developed a milder colitis, with a body weight loss less than that of mice receiving WT T cells (Fig. 3a). FACS analysis of splenic and intestinal CD4+ T cells revealed a marked increase in IL-4-producing Th2 cells and a decrease in IFN-γ-producing Th1 cells in Rag2−/−γc−/− mice receiving Jmjd3-deficient T cells compared with those receiving WT CD4+ T cells (Fig. 3b). Consistently, IFN-γ-producing Th1 cells were decreased in Rag2−/−γc−/− mice receiving intravenous Jmjd3 cKO naïve CD4+ T cells compared with those receiving WT CD4+ T cells (Fig. 3c). To further determine the role of Jmjd3-deficient Th1 cells in the colitis models with or without Treg cells from WT and Jmjd3-deficient mice, we isolated and transferred WT or Jmjd3-deficient CD4+ T cells into lymphopenic Rag2−/−γc−/− mice, and measured percent initial body weight change. Consistent with our findings in Fig. 3a, Jmjd3-deficient T cells limited colitis in Rag2−/−γc−/− mice (Fig. 3d). To determine whether Jmjd3 deficiency affects Treg cell suppressive function in the Th1-mediated colitis model, we isolated and transferred WT and Jmjd3-deficient Treg cells together with naïve WT CD4+ T cells into lymphopenic Rag2−/−γc−/− mice. Co-transfer of both naïve CD4+ T cells and Treg cells suppressed weight loss and decreased colitis score at 40 days post-cell transfer regardless of whether the Treg cells were derived from WT or Jmjd3-deficient mice (Fig. 3d, 3e, 3f). Jmjd3 ablation inhibits Th1 differentiation and promotes Th2 differentiation in an in vivo colitis model, but does not affect the suppressive function of Treg cells.

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