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Anti-proliferative Activity of T-bet.

Oh YJ, Shin JH, Won HY, Hwang ES - Immune Netw (2015)

Bottom Line: Therefore, we examined the effect of T-bet on Th cell proliferation and found that T-bet deficiency significantly enhanced Th cell proliferation under non-skewing, Th1-skewing, and Th2-skewing conditions.By using IFN-γ- mice to eliminate the anti-proliferative effect of IFN-γ, T-bet deficiency still enhanced Th cell proliferation under both Th1- and Th2-skewing conditions.We demonstrated that T-bet expression induced by ecdysone treatment in human embryonic kidney (HEK) cells increased IFN-γ promoter activity in a dose dependent manner, and sustained T-bet expression considerably decreased cell proliferation in HEK cells.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.

ABSTRACT
T-bet is a critical transcription factor that regulates differentiation of Th1 cells from CD4(+) precursor cells. Since T-bet directly binds to the promoter of the IFN-γ gene and activates its transcription, T-bet deficiency impairs IFN-γ production in Th1 cells. Interestingly, T-bet-deficient Th cells also display substantially augmented the production of IL-2, a T cell growth factor. Exogenous expression of T-bet in T-bet deficient Th cells rescued the IFN-γ production and suppressed IL-2 expression. IFN-γ and IL-2 reciprocally regulate Th cell proliferation following TCR stimulation. Therefore, we examined the effect of T-bet on Th cell proliferation and found that T-bet deficiency significantly enhanced Th cell proliferation under non-skewing, Th1-skewing, and Th2-skewing conditions. By using IFN-γ- mice to eliminate the anti-proliferative effect of IFN-γ, T-bet deficiency still enhanced Th cell proliferation under both Th1- and Th2-skewing conditions. Since the anti-proliferative activity of T-bet may be influenced by IL-2 suppression in Th cells, we examined whether T-bet modulates IL-2-independent cell proliferation in a non-T cell population. We demonstrated that T-bet expression induced by ecdysone treatment in human embryonic kidney (HEK) cells increased IFN-γ promoter activity in a dose dependent manner, and sustained T-bet expression considerably decreased cell proliferation in HEK cells. Although the molecular mechanisms underlying anti-proliferative activity of T-bet remain to be elucidated, T-bet may directly suppress cell proliferation in an IFN-γ- or an IL-2-independent manner.

No MeSH data available.


Related in: MedlinePlus

Effect of T-bet on Th1 and Th2 cell proliferation. CD4+ Th cells isolated from WT and T-bet KO mice were activated using anti-CD3 and differentiated into Th1 and Th2 cells in the presence (+) or absence (-) of exogenous rhIL-2. Developing Th1 and Th2 cells were incubated with 3H-thymidine to determine cell proliferation rate. Y-axes represent count per minute (CPM). A total of 6 mice per group were analyzed and data are presented as the average ±SD of 3 experiments. *p<0.05, **p<0.005, ***p<0.0005.
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Figure 2: Effect of T-bet on Th1 and Th2 cell proliferation. CD4+ Th cells isolated from WT and T-bet KO mice were activated using anti-CD3 and differentiated into Th1 and Th2 cells in the presence (+) or absence (-) of exogenous rhIL-2. Developing Th1 and Th2 cells were incubated with 3H-thymidine to determine cell proliferation rate. Y-axes represent count per minute (CPM). A total of 6 mice per group were analyzed and data are presented as the average ±SD of 3 experiments. *p<0.05, **p<0.005, ***p<0.0005.

Mentions: Since T-bet expression is increased by treatment with IL-12 during Th cell differentiation, CD4+ Th cells from WT and T-bet KO mice were stimulated with anti-CD3 Ab and then cultured for 2 days with Th1-skewing cytokines. Like in non-skewing conditions, developing T-bet- Th1 cells are more proliferative than WT Th cells (Fig. 2A). Exogenous rhIL-2 addition caused no change in cell proliferation of developing Th1 cells (Fig. 2B). Because T-bet deficiency induces Th2 cytokine production, we skewed the cells with IL-4 cytokine to eliminate the developmental difference between WT and T-bet KO Th cells. In response to anti-CD3 stimulation, developing Th2 cells were much more proliferative compared to cells in either non-skewing or Th1-skewing conditions (Fig. 2C). Additionally, T-bet KO Th2 cells are more proliferative than WT cells regardless of IL-2 presence (Fig. 2C and D). These results suggest that T-bet deficiency promotes Th cell proliferation in response to TCR stimulation during Th cell development into both Th1 and Th2 cells.


Anti-proliferative Activity of T-bet.

Oh YJ, Shin JH, Won HY, Hwang ES - Immune Netw (2015)

Effect of T-bet on Th1 and Th2 cell proliferation. CD4+ Th cells isolated from WT and T-bet KO mice were activated using anti-CD3 and differentiated into Th1 and Th2 cells in the presence (+) or absence (-) of exogenous rhIL-2. Developing Th1 and Th2 cells were incubated with 3H-thymidine to determine cell proliferation rate. Y-axes represent count per minute (CPM). A total of 6 mice per group were analyzed and data are presented as the average ±SD of 3 experiments. *p<0.05, **p<0.005, ***p<0.0005.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4553258&req=5

Figure 2: Effect of T-bet on Th1 and Th2 cell proliferation. CD4+ Th cells isolated from WT and T-bet KO mice were activated using anti-CD3 and differentiated into Th1 and Th2 cells in the presence (+) or absence (-) of exogenous rhIL-2. Developing Th1 and Th2 cells were incubated with 3H-thymidine to determine cell proliferation rate. Y-axes represent count per minute (CPM). A total of 6 mice per group were analyzed and data are presented as the average ±SD of 3 experiments. *p<0.05, **p<0.005, ***p<0.0005.
Mentions: Since T-bet expression is increased by treatment with IL-12 during Th cell differentiation, CD4+ Th cells from WT and T-bet KO mice were stimulated with anti-CD3 Ab and then cultured for 2 days with Th1-skewing cytokines. Like in non-skewing conditions, developing T-bet- Th1 cells are more proliferative than WT Th cells (Fig. 2A). Exogenous rhIL-2 addition caused no change in cell proliferation of developing Th1 cells (Fig. 2B). Because T-bet deficiency induces Th2 cytokine production, we skewed the cells with IL-4 cytokine to eliminate the developmental difference between WT and T-bet KO Th cells. In response to anti-CD3 stimulation, developing Th2 cells were much more proliferative compared to cells in either non-skewing or Th1-skewing conditions (Fig. 2C). Additionally, T-bet KO Th2 cells are more proliferative than WT cells regardless of IL-2 presence (Fig. 2C and D). These results suggest that T-bet deficiency promotes Th cell proliferation in response to TCR stimulation during Th cell development into both Th1 and Th2 cells.

Bottom Line: Therefore, we examined the effect of T-bet on Th cell proliferation and found that T-bet deficiency significantly enhanced Th cell proliferation under non-skewing, Th1-skewing, and Th2-skewing conditions.By using IFN-γ- mice to eliminate the anti-proliferative effect of IFN-γ, T-bet deficiency still enhanced Th cell proliferation under both Th1- and Th2-skewing conditions.We demonstrated that T-bet expression induced by ecdysone treatment in human embryonic kidney (HEK) cells increased IFN-γ promoter activity in a dose dependent manner, and sustained T-bet expression considerably decreased cell proliferation in HEK cells.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea.

ABSTRACT
T-bet is a critical transcription factor that regulates differentiation of Th1 cells from CD4(+) precursor cells. Since T-bet directly binds to the promoter of the IFN-γ gene and activates its transcription, T-bet deficiency impairs IFN-γ production in Th1 cells. Interestingly, T-bet-deficient Th cells also display substantially augmented the production of IL-2, a T cell growth factor. Exogenous expression of T-bet in T-bet deficient Th cells rescued the IFN-γ production and suppressed IL-2 expression. IFN-γ and IL-2 reciprocally regulate Th cell proliferation following TCR stimulation. Therefore, we examined the effect of T-bet on Th cell proliferation and found that T-bet deficiency significantly enhanced Th cell proliferation under non-skewing, Th1-skewing, and Th2-skewing conditions. By using IFN-γ- mice to eliminate the anti-proliferative effect of IFN-γ, T-bet deficiency still enhanced Th cell proliferation under both Th1- and Th2-skewing conditions. Since the anti-proliferative activity of T-bet may be influenced by IL-2 suppression in Th cells, we examined whether T-bet modulates IL-2-independent cell proliferation in a non-T cell population. We demonstrated that T-bet expression induced by ecdysone treatment in human embryonic kidney (HEK) cells increased IFN-γ promoter activity in a dose dependent manner, and sustained T-bet expression considerably decreased cell proliferation in HEK cells. Although the molecular mechanisms underlying anti-proliferative activity of T-bet remain to be elucidated, T-bet may directly suppress cell proliferation in an IFN-γ- or an IL-2-independent manner.

No MeSH data available.


Related in: MedlinePlus