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Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice.

Zhao H, Yan M, Wang H, Erickson S, Grewal IS, Dixit VM - J. Exp. Med. (2001)

Bottom Line: In addition, DR6(-/)- T cells showed preference toward Th2 differentiation in vitro.Therefore, DR6, working through JNK, rather than apoptosis, functions to attenuate the Th2 response.This is the first demonstration of a role in the activation and differentiation of Th cells by DR6 in particular and DRs in general.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

ABSTRACT
During an immune response naive T helper (Th) cells differentiate into two functionally distinct subsets, Th1 and Th2, based on their cytokine secretion profile and immunomodulatory function. c-Jun amino terminal kinase (JNK) regulates Th cell differentiation by activating a transcriptional program required for cytokine production. We have recently identified a TNFR superfamily death domain-containing molecule, death receptor (DR)6, which potently activates JNK. T cells from DR6-deficient mice are substantially impaired in JNK activation. When DR6(-/-) mice were challenged with protein antigen, their T cells hyperproliferate and display a profound polarization toward a Th2 response whereas Th1 differentiation is not equivalently affected. In addition, DR6(-/)- T cells showed preference toward Th2 differentiation in vitro. The phenotype seen in the DR6(-/)- mice is not due to the apoptotic pathway. Therefore, DR6, working through JNK, rather than apoptosis, functions to attenuate the Th2 response. This is the first demonstration of a role in the activation and differentiation of Th cells by DR6 in particular and DRs in general.

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In vitro induction of Th cell differentiation and effect of DR6 on cell death. T cells purified from spleens of wild-type (black bars) or DR6-deficient (white bars) mice were differentiated into Th1 or Th2 cells with anti-CD3 plus anti-CD28. Production of IFN-γ and IL-4 was determined by ELISA. Data represent the mean SD of pools of five mice per group. ND, not detected.
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fig7: In vitro induction of Th cell differentiation and effect of DR6 on cell death. T cells purified from spleens of wild-type (black bars) or DR6-deficient (white bars) mice were differentiated into Th1 or Th2 cells with anti-CD3 plus anti-CD28. Production of IFN-γ and IL-4 was determined by ELISA. Data represent the mean SD of pools of five mice per group. ND, not detected.

Mentions: Since DR6-deficient mice exhibited an enhanced Th2 response in vivo, we investigated the role of DR6 in mediating Th differentiation in vitro. Purified naive CD4+ T cells from wild-type and DR6-deficient mice were differentiated into either Th1 cells by activating them with α-CD3 plus α-CD28 in the presence of antibodies to IL-12 and IL-4 or into Th2 cells in the presence of IL-4 and antibody to IFN-γ. When differentiated into Th1 cells, DR6-deficient lymphocytes produced levels of IFN-γ equivalent to wild-type controls (Fig. 7). In contrast, DR6-deficient lymphocytes grown in the presence of IL-4 and anti–IFN-γ produced markedly enhanced Th2 cytokines such as IL-4 itself. Cytokine production was also determined by staining the T cells for intracellular IFN-γ and IL-4. A significantly higher number of T cells produced IL-4 (data not shown), indicating that the IL-4 producing T cells pool was expanded in DR6−/− mice. Taken together, our results indicate that DR6 plays a major role in Th cell differentiation both in vivo and in vitro.


Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice.

Zhao H, Yan M, Wang H, Erickson S, Grewal IS, Dixit VM - J. Exp. Med. (2001)

In vitro induction of Th cell differentiation and effect of DR6 on cell death. T cells purified from spleens of wild-type (black bars) or DR6-deficient (white bars) mice were differentiated into Th1 or Th2 cells with anti-CD3 plus anti-CD28. Production of IFN-γ and IL-4 was determined by ELISA. Data represent the mean SD of pools of five mice per group. ND, not detected.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193683&req=5

fig7: In vitro induction of Th cell differentiation and effect of DR6 on cell death. T cells purified from spleens of wild-type (black bars) or DR6-deficient (white bars) mice were differentiated into Th1 or Th2 cells with anti-CD3 plus anti-CD28. Production of IFN-γ and IL-4 was determined by ELISA. Data represent the mean SD of pools of five mice per group. ND, not detected.
Mentions: Since DR6-deficient mice exhibited an enhanced Th2 response in vivo, we investigated the role of DR6 in mediating Th differentiation in vitro. Purified naive CD4+ T cells from wild-type and DR6-deficient mice were differentiated into either Th1 cells by activating them with α-CD3 plus α-CD28 in the presence of antibodies to IL-12 and IL-4 or into Th2 cells in the presence of IL-4 and antibody to IFN-γ. When differentiated into Th1 cells, DR6-deficient lymphocytes produced levels of IFN-γ equivalent to wild-type controls (Fig. 7). In contrast, DR6-deficient lymphocytes grown in the presence of IL-4 and anti–IFN-γ produced markedly enhanced Th2 cytokines such as IL-4 itself. Cytokine production was also determined by staining the T cells for intracellular IFN-γ and IL-4. A significantly higher number of T cells produced IL-4 (data not shown), indicating that the IL-4 producing T cells pool was expanded in DR6−/− mice. Taken together, our results indicate that DR6 plays a major role in Th cell differentiation both in vivo and in vitro.

Bottom Line: In addition, DR6(-/)- T cells showed preference toward Th2 differentiation in vitro.Therefore, DR6, working through JNK, rather than apoptosis, functions to attenuate the Th2 response.This is the first demonstration of a role in the activation and differentiation of Th cells by DR6 in particular and DRs in general.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

ABSTRACT
During an immune response naive T helper (Th) cells differentiate into two functionally distinct subsets, Th1 and Th2, based on their cytokine secretion profile and immunomodulatory function. c-Jun amino terminal kinase (JNK) regulates Th cell differentiation by activating a transcriptional program required for cytokine production. We have recently identified a TNFR superfamily death domain-containing molecule, death receptor (DR)6, which potently activates JNK. T cells from DR6-deficient mice are substantially impaired in JNK activation. When DR6(-/-) mice were challenged with protein antigen, their T cells hyperproliferate and display a profound polarization toward a Th2 response whereas Th1 differentiation is not equivalently affected. In addition, DR6(-/)- T cells showed preference toward Th2 differentiation in vitro. The phenotype seen in the DR6(-/)- mice is not due to the apoptotic pathway. Therefore, DR6, working through JNK, rather than apoptosis, functions to attenuate the Th2 response. This is the first demonstration of a role in the activation and differentiation of Th cells by DR6 in particular and DRs in general.

Show MeSH