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Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells.

Rincón M, Anguita J, Nakamura T, Fikrig E, Flavell RA - J. Exp. Med. (1997)

Bottom Line: However, the source of the initial polarizing IL-4 remains unclear.Here, we show that IL-6, probably secreted by antigen-presenting cells, is able to polarize naive CD4+ T cells to effector Th2 cells by inducing the initial production of IL-4 in CD4+ T cells.These results show that the nature of the cytokine (IL-12 or IL-6), which is produced by antigen-presenting cells in response to a particular pathogen, is a key factor in determining the nature of the immune response.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8011, USA.

ABSTRACT
Interleukin (IL)-4 is the most potent factor that causes naive CD4+ T cells to differentiate to the T helper cell (Th) 2 phenotype, while IL-12 and interferon gamma trigger the differentiation of Th1 cells. However, the source of the initial polarizing IL-4 remains unclear. Here, we show that IL-6, probably secreted by antigen-presenting cells, is able to polarize naive CD4+ T cells to effector Th2 cells by inducing the initial production of IL-4 in CD4+ T cells. These results show that the nature of the cytokine (IL-12 or IL-6), which is produced by antigen-presenting cells in response to a particular pathogen, is a key factor in determining the nature of the immune response.

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Schematic model for the differentiation of precursors Th cells (pTh) into effector Th1 and Th2 cells.
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Figure 4: Schematic model for the differentiation of precursors Th cells (pTh) into effector Th1 and Th2 cells.

Mentions: Both in vivo and in vitro experiments support the idea that, although other factors can play immunomodulatory roles, IL-4 and IL-12 are both necessary and sufficient for the polarization of Th1 and Th2 during the response to different pathogens. Considerable interest in the initial source of the IL-4 that drives Th2 cell differentiation has been expressed and recent attention has focused on mast cells or NK1.1+ CD4 T cells. We propose here that IL-6 is one of the stimuli in the initial production of IL-4 which provides a new mechanism to initiate Th2 CD4+ T cell differentiation. The levels of IL-6 that we used in these experiments are relatively high, just as the levels of IL-4 that also must be used to direct Th2 differentiation in vitro are (500– 1,000 U/ml IL-4). Presumably, for both IL-4 and IL-6 produced endogenously, lower levels produced in a local microenvironment suffice. Consistent with this idea, although the IL-6 effect is mediated through IL-4 (since it is blocked by anti–IL-4), the levels of IL-4 that can be detected are very low, presumably because of local consumption, but are sufficient to direct Th2 cell differentiation. Our data suggest a model (Fig. 4) for Th2 differentiation that is strikingly similar to the mechanism used for Th1 differentiation. In both cases, the source of the polarizing cytokine is the APC, IL-12 in the case of Th1 cells and IL-6 in the case of Th2 cells. Although APCs are the major source of IL-6 in vitro, other cell types that produce IL-6, such as fibroblasts, endothelial cells, keratinocytes or others, could also contribute to the overall in vivo IL-6 production. In our in vitro model, activation of the APC is proposed to result in the secretion of IL-6 which, in combination with the antigen, will participate in the induction of IL-4 gene expression in naive CD4+ T cells. In the second step, the low levels of IL-4 secreted by the T cells is sufficient to induce upregulation of the IL-4 and IL-4 receptor genes in an autocrine manner, while it inhibits the expression of the IFN-γ gene. Cells are therefore subsequently polarized to a Th2 phenotype using their own source of IL-4.


Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells.

Rincón M, Anguita J, Nakamura T, Fikrig E, Flavell RA - J. Exp. Med. (1997)

Schematic model for the differentiation of precursors Th cells (pTh) into effector Th1 and Th2 cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196041&req=5

Figure 4: Schematic model for the differentiation of precursors Th cells (pTh) into effector Th1 and Th2 cells.
Mentions: Both in vivo and in vitro experiments support the idea that, although other factors can play immunomodulatory roles, IL-4 and IL-12 are both necessary and sufficient for the polarization of Th1 and Th2 during the response to different pathogens. Considerable interest in the initial source of the IL-4 that drives Th2 cell differentiation has been expressed and recent attention has focused on mast cells or NK1.1+ CD4 T cells. We propose here that IL-6 is one of the stimuli in the initial production of IL-4 which provides a new mechanism to initiate Th2 CD4+ T cell differentiation. The levels of IL-6 that we used in these experiments are relatively high, just as the levels of IL-4 that also must be used to direct Th2 differentiation in vitro are (500– 1,000 U/ml IL-4). Presumably, for both IL-4 and IL-6 produced endogenously, lower levels produced in a local microenvironment suffice. Consistent with this idea, although the IL-6 effect is mediated through IL-4 (since it is blocked by anti–IL-4), the levels of IL-4 that can be detected are very low, presumably because of local consumption, but are sufficient to direct Th2 cell differentiation. Our data suggest a model (Fig. 4) for Th2 differentiation that is strikingly similar to the mechanism used for Th1 differentiation. In both cases, the source of the polarizing cytokine is the APC, IL-12 in the case of Th1 cells and IL-6 in the case of Th2 cells. Although APCs are the major source of IL-6 in vitro, other cell types that produce IL-6, such as fibroblasts, endothelial cells, keratinocytes or others, could also contribute to the overall in vivo IL-6 production. In our in vitro model, activation of the APC is proposed to result in the secretion of IL-6 which, in combination with the antigen, will participate in the induction of IL-4 gene expression in naive CD4+ T cells. In the second step, the low levels of IL-4 secreted by the T cells is sufficient to induce upregulation of the IL-4 and IL-4 receptor genes in an autocrine manner, while it inhibits the expression of the IFN-γ gene. Cells are therefore subsequently polarized to a Th2 phenotype using their own source of IL-4.

Bottom Line: However, the source of the initial polarizing IL-4 remains unclear.Here, we show that IL-6, probably secreted by antigen-presenting cells, is able to polarize naive CD4+ T cells to effector Th2 cells by inducing the initial production of IL-4 in CD4+ T cells.These results show that the nature of the cytokine (IL-12 or IL-6), which is produced by antigen-presenting cells in response to a particular pathogen, is a key factor in determining the nature of the immune response.

View Article: PubMed Central - PubMed

Affiliation: Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8011, USA.

ABSTRACT
Interleukin (IL)-4 is the most potent factor that causes naive CD4+ T cells to differentiate to the T helper cell (Th) 2 phenotype, while IL-12 and interferon gamma trigger the differentiation of Th1 cells. However, the source of the initial polarizing IL-4 remains unclear. Here, we show that IL-6, probably secreted by antigen-presenting cells, is able to polarize naive CD4+ T cells to effector Th2 cells by inducing the initial production of IL-4 in CD4+ T cells. These results show that the nature of the cytokine (IL-12 or IL-6), which is produced by antigen-presenting cells in response to a particular pathogen, is a key factor in determining the nature of the immune response.

Show MeSH