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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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Regulation of IL-6  secretion by APCs during the  differentiation of Th1 and Th2  CD4+ T cells. (A) Total CD4+  T cells (B10.BR) were stimulated with Con A (2.5 μg/ml)  plus IL-4 (103 U/ml) or IL-12  (3.5 ng/ml) in the presence of  APCs. Supernatants were harvested at different times of stimulation (day 2, 3, or 4) and IL-6  secretion was analyzed. (B) Total  CD4+ T cells were stimulated as  described in A, but in the presence of anti–IL-6Rα chain mAb  (10 μg/ml). The arrow indicates  the production of IL-6 after 4 d  of stimulation with Con A and  IL-4, in the absence of anti–IL6Rα mAb. (C) Expression of IL6Rα during the differentiation  of Th1 and Th2 cells. CD4+ T  cells unstimulated (day 0) or  stimulated in the presence of  APCs, with Con A plus IL-4  (Con A/IL-4) or IL-12 (Con A/ IL-12) for different periods of  time (day 1, 2, or 4) were harvested, stained with anti-CD4  and anti–IL-6Rα mAbs, and analyzed by FACS®. Fluorescence  profiles show the expression of  IL-6Rα in the CD4+ population.
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Figure 2: Regulation of IL-6 secretion by APCs during the differentiation of Th1 and Th2 CD4+ T cells. (A) Total CD4+ T cells (B10.BR) were stimulated with Con A (2.5 μg/ml) plus IL-4 (103 U/ml) or IL-12 (3.5 ng/ml) in the presence of APCs. Supernatants were harvested at different times of stimulation (day 2, 3, or 4) and IL-6 secretion was analyzed. (B) Total CD4+ T cells were stimulated as described in A, but in the presence of anti–IL-6Rα chain mAb (10 μg/ml). The arrow indicates the production of IL-6 after 4 d of stimulation with Con A and IL-4, in the absence of anti–IL6Rα mAb. (C) Expression of IL6Rα during the differentiation of Th1 and Th2 cells. CD4+ T cells unstimulated (day 0) or stimulated in the presence of APCs, with Con A plus IL-4 (Con A/IL-4) or IL-12 (Con A/ IL-12) for different periods of time (day 1, 2, or 4) were harvested, stained with anti-CD4 and anti–IL-6Rα mAbs, and analyzed by FACS®. Fluorescence profiles show the expression of IL-6Rα in the CD4+ population.

Mentions: As mentioned above, APCs represent the major source of IL-6 early in the immune response. To examine the physiological role of IL-6 in T cell differentiation, we first measured the production of IL-6 during the differentiation of Th1 and Th2 cells. CD4+ T cells were stimulated with Con A and IL-4 or IL-12 in the presence of APCs, and supernatants were harvested after different periods of time to measure IL-6 secretion. After 2 d of culture, identical levels of IL-6 were detected in the IL-4 and IL-12 cultures (Fig. 2 A). However, while the IL-6 level in the presence of IL-12 was sustained during the course of T cell differentiation, it decayed dramatically during the differentiation of Th2 cells in the presence of IL-4. No IL-6 was detected after restimulation of either Th1 or Th2 cells with Con A in the absence of APCs (data not shown), suggesting that the IL-6 that we detected during the first stimulation was secreted mainly by the APCs. The difference in the kinetics of IL-6 synthesis during the differentiation of Th1 and Th2 could, therefore, be due either to upregulation of IL-6 on the APCs in the presence of IL-12, or greater IL-6 consumption by Th2 cells than by Th1 cells. To test this, we examined IL-6 production during the differentiation of Th1 and Th2 in the presence of an anti–IL-6 receptor (IL-6R) mAb, to block IL-6 consumption. In the presence of anti– IL-6R mAb IL-6 did not diminish during the differentiation of Th2 cells (Fig. 2 B). These data indicate that the IL-6 produced by APCs was consumed during the differentiation of Th2 cells, but not during differentiation of Th1 cells, supporting the idea that IL-6 plays a role during Th2 polarization by acting directly on T cells. IL-6R is a heterodimer of the signal transducer gp130 (which is also a component of the IL-11, ciliary neurotrophic factor, leukemia inhibitory factor, and onconstatin M receptors) and the specific IL-6Rα chain (25–30). IL-6R has been found in both unstimulated CD4+ and CD8+ T cell subsets and its expression is downregulated upon activation (31). Differential expression of the IL-6Rα chain during Th1 or Th2 differentiation could explain the higher IL-6 consumption by the Th2 cells. We also analyzed, therefore, the expression of IL-6Rα during the differentiation of CD4+ T cells in effector Th1 or Th2 cells. However, the expression of cell surface IL-6Rα was regulated similarly during the differentiation of Th1 or Th2 cells in the presence of either IL-4 or -12 (Fig. 2 C). Low levels of IL-6Rα were present on unstimulated CD4+ T cells, and downmodulation occurred after the first day of stimulation, remaining at almost undetectable levels during the differentiation of both Th1 and Th2 cells. These results indicated that the effects of IL-6 in the differentiation of Th2 cells were not due to a differential distribution of the IL-6Rα.


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)

Regulation of IL-6  secretion by APCs during the  differentiation of Th1 and Th2  CD4+ T cells. (A) Total CD4+  T cells (B10.BR) were stimulated with Con A (2.5 μg/ml)  plus IL-4 (103 U/ml) or IL-12  (3.5 ng/ml) in the presence of  APCs. Supernatants were harvested at different times of stimulation (day 2, 3, or 4) and IL-6  secretion was analyzed. (B) Total  CD4+ T cells were stimulated as  described in A, but in the presence of anti–IL-6Rα chain mAb  (10 μg/ml). The arrow indicates  the production of IL-6 after 4 d  of stimulation with Con A and  IL-4, in the absence of anti–IL6Rα mAb. (C) Expression of IL6Rα during the differentiation  of Th1 and Th2 cells. CD4+ T  cells unstimulated (day 0) or  stimulated in the presence of  APCs, with Con A plus IL-4  (Con A/IL-4) or IL-12 (Con A/ IL-12) for different periods of  time (day 1, 2, or 4) were harvested, stained with anti-CD4  and anti–IL-6Rα mAbs, and analyzed by FACS®. Fluorescence  profiles show the expression of  IL-6Rα in the CD4+ population.
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Related In: Results  -  Collection

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Figure 2: Regulation of IL-6 secretion by APCs during the differentiation of Th1 and Th2 CD4+ T cells. (A) Total CD4+ T cells (B10.BR) were stimulated with Con A (2.5 μg/ml) plus IL-4 (103 U/ml) or IL-12 (3.5 ng/ml) in the presence of APCs. Supernatants were harvested at different times of stimulation (day 2, 3, or 4) and IL-6 secretion was analyzed. (B) Total CD4+ T cells were stimulated as described in A, but in the presence of anti–IL-6Rα chain mAb (10 μg/ml). The arrow indicates the production of IL-6 after 4 d of stimulation with Con A and IL-4, in the absence of anti–IL6Rα mAb. (C) Expression of IL6Rα during the differentiation of Th1 and Th2 cells. CD4+ T cells unstimulated (day 0) or stimulated in the presence of APCs, with Con A plus IL-4 (Con A/IL-4) or IL-12 (Con A/ IL-12) for different periods of time (day 1, 2, or 4) were harvested, stained with anti-CD4 and anti–IL-6Rα mAbs, and analyzed by FACS®. Fluorescence profiles show the expression of IL-6Rα in the CD4+ population.
Mentions: As mentioned above, APCs represent the major source of IL-6 early in the immune response. To examine the physiological role of IL-6 in T cell differentiation, we first measured the production of IL-6 during the differentiation of Th1 and Th2 cells. CD4+ T cells were stimulated with Con A and IL-4 or IL-12 in the presence of APCs, and supernatants were harvested after different periods of time to measure IL-6 secretion. After 2 d of culture, identical levels of IL-6 were detected in the IL-4 and IL-12 cultures (Fig. 2 A). However, while the IL-6 level in the presence of IL-12 was sustained during the course of T cell differentiation, it decayed dramatically during the differentiation of Th2 cells in the presence of IL-4. No IL-6 was detected after restimulation of either Th1 or Th2 cells with Con A in the absence of APCs (data not shown), suggesting that the IL-6 that we detected during the first stimulation was secreted mainly by the APCs. The difference in the kinetics of IL-6 synthesis during the differentiation of Th1 and Th2 could, therefore, be due either to upregulation of IL-6 on the APCs in the presence of IL-12, or greater IL-6 consumption by Th2 cells than by Th1 cells. To test this, we examined IL-6 production during the differentiation of Th1 and Th2 in the presence of an anti–IL-6 receptor (IL-6R) mAb, to block IL-6 consumption. In the presence of anti– IL-6R mAb IL-6 did not diminish during the differentiation of Th2 cells (Fig. 2 B). These data indicate that the IL-6 produced by APCs was consumed during the differentiation of Th2 cells, but not during differentiation of Th1 cells, supporting the idea that IL-6 plays a role during Th2 polarization by acting directly on T cells. IL-6R is a heterodimer of the signal transducer gp130 (which is also a component of the IL-11, ciliary neurotrophic factor, leukemia inhibitory factor, and onconstatin M receptors) and the specific IL-6Rα chain (25–30). IL-6R has been found in both unstimulated CD4+ and CD8+ T cell subsets and its expression is downregulated upon activation (31). Differential expression of the IL-6Rα chain during Th1 or Th2 differentiation could explain the higher IL-6 consumption by the Th2 cells. We also analyzed, therefore, the expression of IL-6Rα during the differentiation of CD4+ T cells in effector Th1 or Th2 cells. However, the expression of cell surface IL-6Rα was regulated similarly during the differentiation of Th1 or Th2 cells in the presence of either IL-4 or -12 (Fig. 2 C). Low levels of IL-6Rα were present on unstimulated CD4+ T cells, and downmodulation occurred after the first day of stimulation, remaining at almost undetectable levels during the differentiation of both Th1 and Th2 cells. These results indicated that the effects of IL-6 in the differentiation of Th2 cells were not due to a differential distribution of the IL-6Rα.

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