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Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene.

Yamashita M, Kuwahara M, Suzuki A, Hirahara K, Shinnaksu R, Hosokawa H, Hasegawa A, Motohashi S, Iwama A, Nakayama T - J. Exp. Med. (2008)

Bottom Line: Among various proapoptotic genes that are regulated by Bmi1, the expression of proapoptotic BH3-only protein Noxa was increased in Bmi1(-/-) effector Th1/Th2 cells.In addition, Bmi1 was required for DNA CpG methylation of the Noxa gene.Thus, Bmi1 controls memory CD4(+) Th1/Th2 cell survival and function through the direct repression of the Noxa gene.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

ABSTRACT
The maintenance of memory T cells is central to the establishment of immunological memory, although molecular details of the process are poorly understood. In the absence of the polycomb group (PcG) gene Bmi1, the number of memory CD4(+) T helper (Th)1/Th2 cells was reduced significantly. Enhanced cell death of Bmi1(-/-) memory Th2 cells was observed both in vivo and in vitro. Among various proapoptotic genes that are regulated by Bmi1, the expression of proapoptotic BH3-only protein Noxa was increased in Bmi1(-/-) effector Th1/Th2 cells. The generation of memory Th2 cells was restored by the deletion of Noxa, but not by Ink4a and Arf. Direct binding of Bmi1 to the Noxa gene locus was accompanied by histone H3-K27 methylation. The recruitment of other PcG gene products and Dnmt1 to the Noxa gene was highly dependent on the expression of Bmi1. In addition, Bmi1 was required for DNA CpG methylation of the Noxa gene. Moreover, memory Th2-dependent airway inflammation was attenuated substantially in the absence of Bmi1. Thus, Bmi1 controls memory CD4(+) Th1/Th2 cell survival and function through the direct repression of the Noxa gene.

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Decreased mucus hyperproduction and airway hyperresponsiveness in Bmi1−/− memory Th2 mice. Bmi1+/+ and Bmi1−/− memory Th2 mice were challenged by inhalation with OVA as in Fig. 5. (A) 1 d after the last OVA inhalation (day 11), the lungs were fixed and stained with periodic-acid-Schiff (PAS). A representative staining pattern is shown. The control represents BALB/c nu/nu mice without Th2 cell transfer. Bars, 100 μm. (B) On day 12, total RNA was prepared from the lung, and the expression of Gob5, Muc5a/c, and Muc 5b (molecular makers for Goblet cell hyperplasia and mucus production) was determined by a quantitative PCR analysis. The relative intensity (/HPRT; mean of three samples) is shown with standard deviations. (C) OVA-induced airway hyperresponsiveness in Bmi1−/− memory Th2 mice. On day 11, the airway hyperresponsiveness in response to increasing doses of methacholine was measured in a whole-body plethysmograph. The mean values (n = 5) are shown with standard deviations. PBS, PBS-inhaled control; OVA, OVA-inhaled. *, P < 0.01. The experiments were performed twice with similar results. (D) On day 11, changes in the RL (left) and the dynamic compliance (Cdyn; right) were assessed. Mean values (six mice per group) are shown with standard deviations. *, P < 0.01; **, P < 0.05.
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fig7: Decreased mucus hyperproduction and airway hyperresponsiveness in Bmi1−/− memory Th2 mice. Bmi1+/+ and Bmi1−/− memory Th2 mice were challenged by inhalation with OVA as in Fig. 5. (A) 1 d after the last OVA inhalation (day 11), the lungs were fixed and stained with periodic-acid-Schiff (PAS). A representative staining pattern is shown. The control represents BALB/c nu/nu mice without Th2 cell transfer. Bars, 100 μm. (B) On day 12, total RNA was prepared from the lung, and the expression of Gob5, Muc5a/c, and Muc 5b (molecular makers for Goblet cell hyperplasia and mucus production) was determined by a quantitative PCR analysis. The relative intensity (/HPRT; mean of three samples) is shown with standard deviations. (C) OVA-induced airway hyperresponsiveness in Bmi1−/− memory Th2 mice. On day 11, the airway hyperresponsiveness in response to increasing doses of methacholine was measured in a whole-body plethysmograph. The mean values (n = 5) are shown with standard deviations. PBS, PBS-inhaled control; OVA, OVA-inhaled. *, P < 0.01. The experiments were performed twice with similar results. (D) On day 11, changes in the RL (left) and the dynamic compliance (Cdyn; right) were assessed. Mean values (six mice per group) are shown with standard deviations. *, P < 0.01; **, P < 0.05.

Mentions: Finally, to examine functional defects in Bmi1−/− memory Th2 mice, we used a memory Th2 cell–dependent allergic airway inflammation model (36). Memory Th2 mice were generated and simply challenged by inhalation with OVA four times. The OVA-specific IgE and IgG1 (Th2-dependent isotypes) antibody production were decreased in the Bmi1−/− memory Th2 mice, whereas only a marginal decrease in the levels of Th1-dependent IgG2a was seen (Fig. 6 A). Next, we examined the levels of airway inflammation after OVA inhalation. The extent of inflammatory leukocyte infiltration in the peri-bronchiolar region (Fig. 6 B) and the infiltrated eosinophils, lymphocytes, and macrophages in the bronchioalveolar lavage (BAL) fluid (Fig. 6 C) was reduced significantly in the Bmi1−/− memory Th2 mice as compared with wild-type mice. The expression of Th2 cytokines (IL-4, IL-5, and IL-13) and Eotaxin 2 in the lung of OVA-inhaled Bmi1−/− memory Th2 mice was also reduced (Fig. 6 D). The periodic-acid-Schiff staining and the measurement of mRNA expression of Gob5, Muc5a/c, and Muc5b in the lung indicated a decrease in mucus hyperproduction in Bmi1−/− memory Th2 mice (Fig. 7, A and B). Furthermore, the airway hyperresponsiveness measured using a whole-body plethysmograph was not significantly induced in the Bmi1−/− memory Th2 mice (Fig. 7 C). In addition, by a direct invasive assay for lung resistance (RL), increase in the RL and decrease in the dynamic compliance were observed in the Bmi1−/− memory Th2 mice (Fig. 7 D). Collectively, these results indicate that the memory Th2 cell–dependent allergic responses were thus compromised in the Bmi1−/− memory Th2 mice. We also assessed the eosinophilic infiltration in DO11.10 Tg Bmi1+/+ and Bmi1+/− mice without cell transfer, and as expected, the level of eosinophilic infiltration was significantly milder in the Bmi1+/− mice (not depicted).


Bmi1 regulates memory CD4 T cell survival via repression of the Noxa gene.

Yamashita M, Kuwahara M, Suzuki A, Hirahara K, Shinnaksu R, Hosokawa H, Hasegawa A, Motohashi S, Iwama A, Nakayama T - J. Exp. Med. (2008)

Decreased mucus hyperproduction and airway hyperresponsiveness in Bmi1−/− memory Th2 mice. Bmi1+/+ and Bmi1−/− memory Th2 mice were challenged by inhalation with OVA as in Fig. 5. (A) 1 d after the last OVA inhalation (day 11), the lungs were fixed and stained with periodic-acid-Schiff (PAS). A representative staining pattern is shown. The control represents BALB/c nu/nu mice without Th2 cell transfer. Bars, 100 μm. (B) On day 12, total RNA was prepared from the lung, and the expression of Gob5, Muc5a/c, and Muc 5b (molecular makers for Goblet cell hyperplasia and mucus production) was determined by a quantitative PCR analysis. The relative intensity (/HPRT; mean of three samples) is shown with standard deviations. (C) OVA-induced airway hyperresponsiveness in Bmi1−/− memory Th2 mice. On day 11, the airway hyperresponsiveness in response to increasing doses of methacholine was measured in a whole-body plethysmograph. The mean values (n = 5) are shown with standard deviations. PBS, PBS-inhaled control; OVA, OVA-inhaled. *, P < 0.01. The experiments were performed twice with similar results. (D) On day 11, changes in the RL (left) and the dynamic compliance (Cdyn; right) were assessed. Mean values (six mice per group) are shown with standard deviations. *, P < 0.01; **, P < 0.05.
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fig7: Decreased mucus hyperproduction and airway hyperresponsiveness in Bmi1−/− memory Th2 mice. Bmi1+/+ and Bmi1−/− memory Th2 mice were challenged by inhalation with OVA as in Fig. 5. (A) 1 d after the last OVA inhalation (day 11), the lungs were fixed and stained with periodic-acid-Schiff (PAS). A representative staining pattern is shown. The control represents BALB/c nu/nu mice without Th2 cell transfer. Bars, 100 μm. (B) On day 12, total RNA was prepared from the lung, and the expression of Gob5, Muc5a/c, and Muc 5b (molecular makers for Goblet cell hyperplasia and mucus production) was determined by a quantitative PCR analysis. The relative intensity (/HPRT; mean of three samples) is shown with standard deviations. (C) OVA-induced airway hyperresponsiveness in Bmi1−/− memory Th2 mice. On day 11, the airway hyperresponsiveness in response to increasing doses of methacholine was measured in a whole-body plethysmograph. The mean values (n = 5) are shown with standard deviations. PBS, PBS-inhaled control; OVA, OVA-inhaled. *, P < 0.01. The experiments were performed twice with similar results. (D) On day 11, changes in the RL (left) and the dynamic compliance (Cdyn; right) were assessed. Mean values (six mice per group) are shown with standard deviations. *, P < 0.01; **, P < 0.05.
Mentions: Finally, to examine functional defects in Bmi1−/− memory Th2 mice, we used a memory Th2 cell–dependent allergic airway inflammation model (36). Memory Th2 mice were generated and simply challenged by inhalation with OVA four times. The OVA-specific IgE and IgG1 (Th2-dependent isotypes) antibody production were decreased in the Bmi1−/− memory Th2 mice, whereas only a marginal decrease in the levels of Th1-dependent IgG2a was seen (Fig. 6 A). Next, we examined the levels of airway inflammation after OVA inhalation. The extent of inflammatory leukocyte infiltration in the peri-bronchiolar region (Fig. 6 B) and the infiltrated eosinophils, lymphocytes, and macrophages in the bronchioalveolar lavage (BAL) fluid (Fig. 6 C) was reduced significantly in the Bmi1−/− memory Th2 mice as compared with wild-type mice. The expression of Th2 cytokines (IL-4, IL-5, and IL-13) and Eotaxin 2 in the lung of OVA-inhaled Bmi1−/− memory Th2 mice was also reduced (Fig. 6 D). The periodic-acid-Schiff staining and the measurement of mRNA expression of Gob5, Muc5a/c, and Muc5b in the lung indicated a decrease in mucus hyperproduction in Bmi1−/− memory Th2 mice (Fig. 7, A and B). Furthermore, the airway hyperresponsiveness measured using a whole-body plethysmograph was not significantly induced in the Bmi1−/− memory Th2 mice (Fig. 7 C). In addition, by a direct invasive assay for lung resistance (RL), increase in the RL and decrease in the dynamic compliance were observed in the Bmi1−/− memory Th2 mice (Fig. 7 D). Collectively, these results indicate that the memory Th2 cell–dependent allergic responses were thus compromised in the Bmi1−/− memory Th2 mice. We also assessed the eosinophilic infiltration in DO11.10 Tg Bmi1+/+ and Bmi1+/− mice without cell transfer, and as expected, the level of eosinophilic infiltration was significantly milder in the Bmi1+/− mice (not depicted).

Bottom Line: Among various proapoptotic genes that are regulated by Bmi1, the expression of proapoptotic BH3-only protein Noxa was increased in Bmi1(-/-) effector Th1/Th2 cells.In addition, Bmi1 was required for DNA CpG methylation of the Noxa gene.Thus, Bmi1 controls memory CD4(+) Th1/Th2 cell survival and function through the direct repression of the Noxa gene.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.

ABSTRACT
The maintenance of memory T cells is central to the establishment of immunological memory, although molecular details of the process are poorly understood. In the absence of the polycomb group (PcG) gene Bmi1, the number of memory CD4(+) T helper (Th)1/Th2 cells was reduced significantly. Enhanced cell death of Bmi1(-/-) memory Th2 cells was observed both in vivo and in vitro. Among various proapoptotic genes that are regulated by Bmi1, the expression of proapoptotic BH3-only protein Noxa was increased in Bmi1(-/-) effector Th1/Th2 cells. The generation of memory Th2 cells was restored by the deletion of Noxa, but not by Ink4a and Arf. Direct binding of Bmi1 to the Noxa gene locus was accompanied by histone H3-K27 methylation. The recruitment of other PcG gene products and Dnmt1 to the Noxa gene was highly dependent on the expression of Bmi1. In addition, Bmi1 was required for DNA CpG methylation of the Noxa gene. Moreover, memory Th2-dependent airway inflammation was attenuated substantially in the absence of Bmi1. Thus, Bmi1 controls memory CD4(+) Th1/Th2 cell survival and function through the direct repression of the Noxa gene.

Show MeSH
Related in: MedlinePlus