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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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IL-6–producing APCs are required for the differentiation of  Th2 cells. (A) Total CD4+ T cells (106/ml) were isolated from WT mice  and stimulated with Con A (2.5 μg/ml) alone in the presence of APCs (5 ×  105 cells/ml) from WT (WT APC) or IL-6–deficient (IL-6−/− APC)  mice. After 4 d, CD4+ T cells were washed and restimulated (106 cells/ml)  with Con A in the absence of APCs, and supernatants were collected after  24 h. (B) Total CD4+ T cells were isolated from IL-6–deficient (IL-6−/−)  mice and stimulated with Con A plus medium (−), neutralizing anti–IL-6  mAb (10 μg/ml) (anti–IL-6), IL-6 (100 ng/ml), IL-4 (103 U/ml), or both  (IL-4 + IL-6), in the presence of APCs from WT (WT APC) or IL-6– deficient (IL-6−/−) mice. After 4 d, cells were washed and restimulated  (106 cells/ml) with Con A alone for 24 h. Only in the case where all cells  (both CD4 T cells and APCs) were from IL-6−/− mice did we observe a  slightly lower recovery (70–80% of the recovery from other conditions)  after 4 d of primary culture. Nevertheless, cell number was normalized  (106 cells/ml) before restimulation. (C) Induction of IL-4 gene expression in CD4+ Th2 cells differentiated in the presence of IL-6. Naive CD4+ T  cells (12) from Cyt c TCR transgenic mice were primary cultured with moth Cyt c peptide (5 μg/ml) and APCs in the absence (−) or the presence of  IL-6 (100 ng/ml) or IL-4 (103 U/ml) for 4 d. Cells were then washed and stimulated with Cyt c peptide and APCs. After 20 h, 2 × 105 cells were harvested and used for the quantitation of IL-4 mRNA by competitive RT-PCR. (Top) The expression of IL-4 transcripts. (Bottom) The expression of DR  transcripts. Small arrow, the competitor DNA.
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Figure 3: IL-6–producing APCs are required for the differentiation of Th2 cells. (A) Total CD4+ T cells (106/ml) were isolated from WT mice and stimulated with Con A (2.5 μg/ml) alone in the presence of APCs (5 × 105 cells/ml) from WT (WT APC) or IL-6–deficient (IL-6−/− APC) mice. After 4 d, CD4+ T cells were washed and restimulated (106 cells/ml) with Con A in the absence of APCs, and supernatants were collected after 24 h. (B) Total CD4+ T cells were isolated from IL-6–deficient (IL-6−/−) mice and stimulated with Con A plus medium (−), neutralizing anti–IL-6 mAb (10 μg/ml) (anti–IL-6), IL-6 (100 ng/ml), IL-4 (103 U/ml), or both (IL-4 + IL-6), in the presence of APCs from WT (WT APC) or IL-6– deficient (IL-6−/−) mice. After 4 d, cells were washed and restimulated (106 cells/ml) with Con A alone for 24 h. Only in the case where all cells (both CD4 T cells and APCs) were from IL-6−/− mice did we observe a slightly lower recovery (70–80% of the recovery from other conditions) after 4 d of primary culture. Nevertheless, cell number was normalized (106 cells/ml) before restimulation. (C) Induction of IL-4 gene expression in CD4+ Th2 cells differentiated in the presence of IL-6. Naive CD4+ T cells (12) from Cyt c TCR transgenic mice were primary cultured with moth Cyt c peptide (5 μg/ml) and APCs in the absence (−) or the presence of IL-6 (100 ng/ml) or IL-4 (103 U/ml) for 4 d. Cells were then washed and stimulated with Cyt c peptide and APCs. After 20 h, 2 × 105 cells were harvested and used for the quantitation of IL-4 mRNA by competitive RT-PCR. (Top) The expression of IL-4 transcripts. (Bottom) The expression of DR transcripts. Small arrow, the competitor DNA.

Mentions: If IL-6 was required for Th2 cell differentiation in vitro, it would follow that T cells from IL-6−/− mice should be incapable of developing Th2 effector cells. The experiments described below show that this appears to be true. In correlation with the previous characterization of IL-6−/− mice (32, 33), analysis of cellular populations in the spleen and thymus did not show any differences between wildtype (WT) and IL-6−/− mice (data not shown), and IL-6−/− mice developed normally. We therefore used splenocytes from IL-6−/− mice as APCs to further establish that the production of endogenous IL-6 by the APC plays a critical role in the polarization of the CD4+ T cells to effector Th2 cells. We purified CD4+ T cells from WT mice and stimulated them for 4 d with Con A in the presence of APCs from WT mice or IL-6−/− mice in the absence of any added exogenous cytokines. Restimulation with Con A resulted in significantly less IL-4 production in cells differentiated in the presence of IL-6−/− than in WT APCs (Fig. 3 A). Although the production of IFN-γ under these conditions (absence of exogenous IL-12) was low, the levels of IFN-γ produced by CD4 cells differentiated in the presence of IL-6−/− APCs were higher than those produced by cells stimulated in the presence of WT APCs (data not shown).


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)

IL-6–producing APCs are required for the differentiation of  Th2 cells. (A) Total CD4+ T cells (106/ml) were isolated from WT mice  and stimulated with Con A (2.5 μg/ml) alone in the presence of APCs (5 ×  105 cells/ml) from WT (WT APC) or IL-6–deficient (IL-6−/− APC)  mice. After 4 d, CD4+ T cells were washed and restimulated (106 cells/ml)  with Con A in the absence of APCs, and supernatants were collected after  24 h. (B) Total CD4+ T cells were isolated from IL-6–deficient (IL-6−/−)  mice and stimulated with Con A plus medium (−), neutralizing anti–IL-6  mAb (10 μg/ml) (anti–IL-6), IL-6 (100 ng/ml), IL-4 (103 U/ml), or both  (IL-4 + IL-6), in the presence of APCs from WT (WT APC) or IL-6– deficient (IL-6−/−) mice. After 4 d, cells were washed and restimulated  (106 cells/ml) with Con A alone for 24 h. Only in the case where all cells  (both CD4 T cells and APCs) were from IL-6−/− mice did we observe a  slightly lower recovery (70–80% of the recovery from other conditions)  after 4 d of primary culture. Nevertheless, cell number was normalized  (106 cells/ml) before restimulation. (C) Induction of IL-4 gene expression in CD4+ Th2 cells differentiated in the presence of IL-6. Naive CD4+ T  cells (12) from Cyt c TCR transgenic mice were primary cultured with moth Cyt c peptide (5 μg/ml) and APCs in the absence (−) or the presence of  IL-6 (100 ng/ml) or IL-4 (103 U/ml) for 4 d. Cells were then washed and stimulated with Cyt c peptide and APCs. After 20 h, 2 × 105 cells were harvested and used for the quantitation of IL-4 mRNA by competitive RT-PCR. (Top) The expression of IL-4 transcripts. (Bottom) The expression of DR  transcripts. Small arrow, the competitor DNA.
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Figure 3: IL-6–producing APCs are required for the differentiation of Th2 cells. (A) Total CD4+ T cells (106/ml) were isolated from WT mice and stimulated with Con A (2.5 μg/ml) alone in the presence of APCs (5 × 105 cells/ml) from WT (WT APC) or IL-6–deficient (IL-6−/− APC) mice. After 4 d, CD4+ T cells were washed and restimulated (106 cells/ml) with Con A in the absence of APCs, and supernatants were collected after 24 h. (B) Total CD4+ T cells were isolated from IL-6–deficient (IL-6−/−) mice and stimulated with Con A plus medium (−), neutralizing anti–IL-6 mAb (10 μg/ml) (anti–IL-6), IL-6 (100 ng/ml), IL-4 (103 U/ml), or both (IL-4 + IL-6), in the presence of APCs from WT (WT APC) or IL-6– deficient (IL-6−/−) mice. After 4 d, cells were washed and restimulated (106 cells/ml) with Con A alone for 24 h. Only in the case where all cells (both CD4 T cells and APCs) were from IL-6−/− mice did we observe a slightly lower recovery (70–80% of the recovery from other conditions) after 4 d of primary culture. Nevertheless, cell number was normalized (106 cells/ml) before restimulation. (C) Induction of IL-4 gene expression in CD4+ Th2 cells differentiated in the presence of IL-6. Naive CD4+ T cells (12) from Cyt c TCR transgenic mice were primary cultured with moth Cyt c peptide (5 μg/ml) and APCs in the absence (−) or the presence of IL-6 (100 ng/ml) or IL-4 (103 U/ml) for 4 d. Cells were then washed and stimulated with Cyt c peptide and APCs. After 20 h, 2 × 105 cells were harvested and used for the quantitation of IL-4 mRNA by competitive RT-PCR. (Top) The expression of IL-4 transcripts. (Bottom) The expression of DR transcripts. Small arrow, the competitor DNA.
Mentions: If IL-6 was required for Th2 cell differentiation in vitro, it would follow that T cells from IL-6−/− mice should be incapable of developing Th2 effector cells. The experiments described below show that this appears to be true. In correlation with the previous characterization of IL-6−/− mice (32, 33), analysis of cellular populations in the spleen and thymus did not show any differences between wildtype (WT) and IL-6−/− mice (data not shown), and IL-6−/− mice developed normally. We therefore used splenocytes from IL-6−/− mice as APCs to further establish that the production of endogenous IL-6 by the APC plays a critical role in the polarization of the CD4+ T cells to effector Th2 cells. We purified CD4+ T cells from WT mice and stimulated them for 4 d with Con A in the presence of APCs from WT mice or IL-6−/− mice in the absence of any added exogenous cytokines. Restimulation with Con A resulted in significantly less IL-4 production in cells differentiated in the presence of IL-6−/− than in WT APCs (Fig. 3 A). Although the production of IFN-γ under these conditions (absence of exogenous IL-12) was low, the levels of IFN-γ produced by CD4 cells differentiated in the presence of IL-6−/− APCs were higher than those produced by cells stimulated in the presence of WT APCs (data not shown).

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
Related in: MedlinePlus