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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

IFN-γ independence of T-bet's anti-proliferation activity. CD4+ Th cells were isolated from IFN-γ KO mice and IFN-γ/T-bet double KO mice and stimulated with anti-CD3 in the either presence (+) or absence (-) of exogenous rhIL-2. Cells were cultured for an additional 2 to 3 days under Th1-skewing (A) or Th2-skewing (B) conditions. Cell proliferation rates of developing Th cells from either T-bet WT or T-bet KO mice established IFN-γ-deficient background were determined using a thymidine incorporation assay. A total of 5 mice per group were used for analysis and data are expressed as the average ±SD. **p<0.005, ***p<0.0005.
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Figure 3: IFN-γ independence of T-bet's anti-proliferation activity. CD4+ Th cells were isolated from IFN-γ KO mice and IFN-γ/T-bet double KO mice and stimulated with anti-CD3 in the either presence (+) or absence (-) of exogenous rhIL-2. Cells were cultured for an additional 2 to 3 days under Th1-skewing (A) or Th2-skewing (B) conditions. Cell proliferation rates of developing Th cells from either T-bet WT or T-bet KO mice established IFN-γ-deficient background were determined using a thymidine incorporation assay. A total of 5 mice per group were used for analysis and data are expressed as the average ±SD. **p<0.005, ***p<0.0005.

Mentions: IFN-γ plays an inhibitory role in regulation of proliferation in immune cells; its production was impaired in T-bet deficient CD4+ Th cells, suggesting that the hyper-proliferative activity of T-bet deficient CD4+ Th cells may be due to diminished production levels of IFN-γ. To assess the IFN-γ dependency in the anti-proliferative activity of T-bet, we examined the effect of T-bet on Th proliferation in an IFN-γ-deficient genetic background. Interestingly, T-bet/IFN-γ double KO mice showed increased proliferation in response to TCR stimulation when compared to IFN-γ single KO mice under both Th1-skewing conditions (Fig. 3A) and Th2-skewing conditions (Fig. 3C). This result was unaffected by exogenous rhIL-2 (Fig. 3B and D). These results imply that the anti-proliferative activity of T-bet is independent of IFN-γ production.


Anti-proliferative Activity of T-bet.

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

IFN-γ independence of T-bet's anti-proliferation activity. CD4+ Th cells were isolated from IFN-γ KO mice and IFN-γ/T-bet double KO mice and stimulated with anti-CD3 in the either presence (+) or absence (-) of exogenous rhIL-2. Cells were cultured for an additional 2 to 3 days under Th1-skewing (A) or Th2-skewing (B) conditions. Cell proliferation rates of developing Th cells from either T-bet WT or T-bet KO mice established IFN-γ-deficient background were determined using a thymidine incorporation assay. A total of 5 mice per group were used for analysis and data are expressed as the average ±SD. **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 3: IFN-γ independence of T-bet's anti-proliferation activity. CD4+ Th cells were isolated from IFN-γ KO mice and IFN-γ/T-bet double KO mice and stimulated with anti-CD3 in the either presence (+) or absence (-) of exogenous rhIL-2. Cells were cultured for an additional 2 to 3 days under Th1-skewing (A) or Th2-skewing (B) conditions. Cell proliferation rates of developing Th cells from either T-bet WT or T-bet KO mice established IFN-γ-deficient background were determined using a thymidine incorporation assay. A total of 5 mice per group were used for analysis and data are expressed as the average ±SD. **p<0.005, ***p<0.0005.
Mentions: IFN-γ plays an inhibitory role in regulation of proliferation in immune cells; its production was impaired in T-bet deficient CD4+ Th cells, suggesting that the hyper-proliferative activity of T-bet deficient CD4+ Th cells may be due to diminished production levels of IFN-γ. To assess the IFN-γ dependency in the anti-proliferative activity of T-bet, we examined the effect of T-bet on Th proliferation in an IFN-γ-deficient genetic background. Interestingly, T-bet/IFN-γ double KO mice showed increased proliferation in response to TCR stimulation when compared to IFN-γ single KO mice under both Th1-skewing conditions (Fig. 3A) and Th2-skewing conditions (Fig. 3C). This result was unaffected by exogenous rhIL-2 (Fig. 3B and D). These results imply that the anti-proliferative activity of T-bet is independent of IFN-γ production.

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