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T helper type 2 cell differentiation occurs in the presence of interleukin 12 receptor beta2 chain expression and signaling.

Nishikomori R, Ehrhardt RO, Strober W - J. Exp. Med. (2000)

Bottom Line: In the latter case, the presence of IL-4 suppressed interferon (IFN)-gamma production 10-100-fold compared with cells cultured in IL-12 alone.These studies show that IL-4-driven Th2 differentiation can occur in the presence of persistent IL-12 signaling and that IL-4 inhibits IFN-gamma production under these circumstances.They also show that established Th2 cells cannot be converted to Th1 cells via IL-12 signaling.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1890, USA.

ABSTRACT
The differentiation of CD4(+) T cells into T helper type 1 (Th1) cells is driven by interleukin (IL)-12 through the IL-12 receptor beta2 (IL-12Rbeta2) chain, whereas differentiation into Th2 cells is driven by IL-4, which downregulates IL-12Rbeta2 chain. We reexamined such differentiation using IL-12Rbeta2 chain transgenic mice. We found that CD4(+) T cells from such mice were able to differentiate into Th2 cells when primed with IL-4 or IL-4 plus IL-12. In the latter case, the presence of IL-4 suppressed interferon (IFN)-gamma production 10-100-fold compared with cells cultured in IL-12 alone. Finally, in studies of the ability of IL-12 to convert Th2 cells bearing a competent IL-12R to the Th1 cells, we showed that: (a) T cells bearing the IL-12Rbeta2 chain transgene and primed under Th2 conditions could not be converted to Th1 cells by repeated restimulation under Th1 conditions; and (b) established Th2 clones transfected with the IL-12Rbeta2 chain construct continued to produce IL-4 when cultured with IL-12. These studies show that IL-4-driven Th2 differentiation can occur in the presence of persistent IL-12 signaling and that IL-4 inhibits IFN-gamma production under these circumstances. They also show that established Th2 cells cannot be converted to Th1 cells via IL-12 signaling.

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(A) IL-12Rβ2 chain expression on CD4+ cells from double transgenic mice (bearing an IL-12Rβ2 chain transgene and an OVA-TCR transgene) and single transgenic mice (bearing an OVA-TCR transgene only). Histograms of gated CD4+ cells are shown. (B) IL-12Rβ2 chain expression on T cell lines primed in vitro. CD4+CD62Lhigh splenocytes from double transgenic mice bearing an IL-12Rβ2 chain transgene and an OVA-TCR transgene (double Tg) and single transgenic mice bearing an OVA-TCR transgene only (single Tg) were stimulated with antigen (OVA peptide) and APCs without any cytokine addition, with IL-4 (200 U/ml), with IL-12 (2 ng/ml), or with IL-4 (200 U/ml) plus IL-12 (2 ng/ml), and stained for IL-12Rβ2 chain on CD4+ cells on day 3, 5, and 7 after priming. Each group of cells was stained with anti–mouse IL-12Rβ2 chain mAb (solid line) and control mAb (dashed line). Histograms of gated CD4+ cells are shown.
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Figure 1: (A) IL-12Rβ2 chain expression on CD4+ cells from double transgenic mice (bearing an IL-12Rβ2 chain transgene and an OVA-TCR transgene) and single transgenic mice (bearing an OVA-TCR transgene only). Histograms of gated CD4+ cells are shown. (B) IL-12Rβ2 chain expression on T cell lines primed in vitro. CD4+CD62Lhigh splenocytes from double transgenic mice bearing an IL-12Rβ2 chain transgene and an OVA-TCR transgene (double Tg) and single transgenic mice bearing an OVA-TCR transgene only (single Tg) were stimulated with antigen (OVA peptide) and APCs without any cytokine addition, with IL-4 (200 U/ml), with IL-12 (2 ng/ml), or with IL-4 (200 U/ml) plus IL-12 (2 ng/ml), and stained for IL-12Rβ2 chain on CD4+ cells on day 3, 5, and 7 after priming. Each group of cells was stained with anti–mouse IL-12Rβ2 chain mAb (solid line) and control mAb (dashed line). Histograms of gated CD4+ cells are shown.

Mentions: In initial studies, we determined the capacity of naive CD4+ T cells that constitutively express the IL-12Rβ2 chain to undergo Th2 cell differentiation (here defined by the ability of the CD4+ T cells to produce IL-4). For this purpose, we constructed IL-12Rβ2 chain transgenic mice expressing the IL-12Rβ2 chain on T cells under the control of the human CD2 promoter/enhancer (the VAhCD2 minigene vector) 2128. As shown in Fig. 1 A, spleen CD4+ T cells from such transgenic mice do in fact manifest constitutive expression of the IL-12Rβ2 chain, as determined by flow cytometric analysis of cells stained with an IL-12Rβ2 chain–specific mAb (PDL-HAM10B9). To obtain CD4+ T cells expressing the IL-12Rβ2 chain transgene that respond to a particular antigen (OVA peptide), we made double transgenic mice by crossing the IL-12Rβ2 chain transgenic mice (backcrossed for two to three generations with Balb/c mice) to DO11.10 Balb/c mice expressing the TCR specific for OVA peptide in the context of I-Ad 29.


T helper type 2 cell differentiation occurs in the presence of interleukin 12 receptor beta2 chain expression and signaling.

Nishikomori R, Ehrhardt RO, Strober W - J. Exp. Med. (2000)

(A) IL-12Rβ2 chain expression on CD4+ cells from double transgenic mice (bearing an IL-12Rβ2 chain transgene and an OVA-TCR transgene) and single transgenic mice (bearing an OVA-TCR transgene only). Histograms of gated CD4+ cells are shown. (B) IL-12Rβ2 chain expression on T cell lines primed in vitro. CD4+CD62Lhigh splenocytes from double transgenic mice bearing an IL-12Rβ2 chain transgene and an OVA-TCR transgene (double Tg) and single transgenic mice bearing an OVA-TCR transgene only (single Tg) were stimulated with antigen (OVA peptide) and APCs without any cytokine addition, with IL-4 (200 U/ml), with IL-12 (2 ng/ml), or with IL-4 (200 U/ml) plus IL-12 (2 ng/ml), and stained for IL-12Rβ2 chain on CD4+ cells on day 3, 5, and 7 after priming. Each group of cells was stained with anti–mouse IL-12Rβ2 chain mAb (solid line) and control mAb (dashed line). Histograms of gated CD4+ cells are shown.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195855&req=5

Figure 1: (A) IL-12Rβ2 chain expression on CD4+ cells from double transgenic mice (bearing an IL-12Rβ2 chain transgene and an OVA-TCR transgene) and single transgenic mice (bearing an OVA-TCR transgene only). Histograms of gated CD4+ cells are shown. (B) IL-12Rβ2 chain expression on T cell lines primed in vitro. CD4+CD62Lhigh splenocytes from double transgenic mice bearing an IL-12Rβ2 chain transgene and an OVA-TCR transgene (double Tg) and single transgenic mice bearing an OVA-TCR transgene only (single Tg) were stimulated with antigen (OVA peptide) and APCs without any cytokine addition, with IL-4 (200 U/ml), with IL-12 (2 ng/ml), or with IL-4 (200 U/ml) plus IL-12 (2 ng/ml), and stained for IL-12Rβ2 chain on CD4+ cells on day 3, 5, and 7 after priming. Each group of cells was stained with anti–mouse IL-12Rβ2 chain mAb (solid line) and control mAb (dashed line). Histograms of gated CD4+ cells are shown.
Mentions: In initial studies, we determined the capacity of naive CD4+ T cells that constitutively express the IL-12Rβ2 chain to undergo Th2 cell differentiation (here defined by the ability of the CD4+ T cells to produce IL-4). For this purpose, we constructed IL-12Rβ2 chain transgenic mice expressing the IL-12Rβ2 chain on T cells under the control of the human CD2 promoter/enhancer (the VAhCD2 minigene vector) 2128. As shown in Fig. 1 A, spleen CD4+ T cells from such transgenic mice do in fact manifest constitutive expression of the IL-12Rβ2 chain, as determined by flow cytometric analysis of cells stained with an IL-12Rβ2 chain–specific mAb (PDL-HAM10B9). To obtain CD4+ T cells expressing the IL-12Rβ2 chain transgene that respond to a particular antigen (OVA peptide), we made double transgenic mice by crossing the IL-12Rβ2 chain transgenic mice (backcrossed for two to three generations with Balb/c mice) to DO11.10 Balb/c mice expressing the TCR specific for OVA peptide in the context of I-Ad 29.

Bottom Line: In the latter case, the presence of IL-4 suppressed interferon (IFN)-gamma production 10-100-fold compared with cells cultured in IL-12 alone.These studies show that IL-4-driven Th2 differentiation can occur in the presence of persistent IL-12 signaling and that IL-4 inhibits IFN-gamma production under these circumstances.They also show that established Th2 cells cannot be converted to Th1 cells via IL-12 signaling.

View Article: PubMed Central - PubMed

Affiliation: Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1890, USA.

ABSTRACT
The differentiation of CD4(+) T cells into T helper type 1 (Th1) cells is driven by interleukin (IL)-12 through the IL-12 receptor beta2 (IL-12Rbeta2) chain, whereas differentiation into Th2 cells is driven by IL-4, which downregulates IL-12Rbeta2 chain. We reexamined such differentiation using IL-12Rbeta2 chain transgenic mice. We found that CD4(+) T cells from such mice were able to differentiate into Th2 cells when primed with IL-4 or IL-4 plus IL-12. In the latter case, the presence of IL-4 suppressed interferon (IFN)-gamma production 10-100-fold compared with cells cultured in IL-12 alone. Finally, in studies of the ability of IL-12 to convert Th2 cells bearing a competent IL-12R to the Th1 cells, we showed that: (a) T cells bearing the IL-12Rbeta2 chain transgene and primed under Th2 conditions could not be converted to Th1 cells by repeated restimulation under Th1 conditions; and (b) established Th2 clones transfected with the IL-12Rbeta2 chain construct continued to produce IL-4 when cultured with IL-12. These studies show that IL-4-driven Th2 differentiation can occur in the presence of persistent IL-12 signaling and that IL-4 inhibits IFN-gamma production under these circumstances. They also show that established Th2 cells cannot be converted to Th1 cells via IL-12 signaling.

Show MeSH
Related in: MedlinePlus