CoChat
Sign Up
Cited by 810T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisCytokine Signaling Pathways and Interactions

The DOI matches its Crossref record; 51 of the 55 references it cites were found in a registry or an index.

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

Open access
Rincón, Mercedes, Anguita, Juan, Nakamura, Tetsuo, Fikrig, Erol, Flavell, Richard A.·1997·The Journal of Experimental Medicine
DOI 10.1084/jem.185.3.461PMC PMC2196041
Open this paper in CoChat — free account

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 γ 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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1084/jem.185.3.461

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 IL-6 directs differentiation of CD4+ T cells into Th2 cells. (A) Total CD4+ T cells (106/ml) were purified from normal B10.BR mice and stimulated (in the presence of 5 × 105 cell/ml syngeneic APCs) with Con A (2.5 μg/ml) alone, Con A plus IL-4 (103 U/ml) or Con A plus IL-12 (3.5 ng/ml), in the absence (−) or presence of IL-6 (100 ng/ml) or IL-2 (50 U/ml). After 4 d, cells were exhaustively washed and restimulated (106 cells/ml) with Con A alone (2.5 μg/ml) in the absence of APCs or additional cytokines. Supernatants were harvested 24 h later and analyzed for IL-4 and IFN-γ production by ELISA. (B) Total CD4+ population was isolated from Cyt c TCR transgenic mice, and the naive CD4+ CD45RBhighCD44low subpopulation was purified by cell sorting. Naive CD4+ T cells were then stimulated with Con A alone, Con A plus IL-4, or Con A plus IL-12, and APCs, in the presence or absence of IL-6. After 4 d, cells were exhaustively washed and restimulated (106 cell/ ml) with Con A alone for 24 h before harvesting the supernatants for cytokine measurement. (C) Naive CD4+CD45RBhighCD44low CD4+ T cells isolated from Cyt c TCR transgenic mice were stimulated with Cyt c peptide and APCs, in the presence of medium, IL-6 (100 ng/ml), or IL-4, (103 U/ml). After 4 d, cells were exhaustively washed and restimulated (106 cell/ml) with Cyt c peptide and APCs for 24 h. (D) Total CD4+ T cells from normal B10.BR mice were stimulated with immobilized anti– CD3 mAb (5 μg/ml) and soluble anti–CD28 (1 μg/ml) in the presence of medium (−), IL-6 (100 ng/ml), or IL-4 (103 U/ml) and, after 4 d, they were restimulated with immobilized anti–CD3 mAb. (E) Total CD4+ T cells from normal B10.BR mice were stimulated with Con A and APCs in the presence of medium (−), IL-6 (100 ng/ml) (IL-6), or IL-6 (100 ng/ml) plus anti–IL-4 mAb (10 μg/ml) (IL-6 + anti–IL-4), for 4 d. Cells were then restimulated (106 cells/ml) with Con A alone as described in A.
Figure 1 IL-6 directs differentiation of CD4+ T cells into Th2 cells. (A) Total CD4+ T cells (106/ml) were purified from normal B10.BR mice and stimulated (in the presence of 5 × 105 cell/ml syngeneic APCs) with Con A (2.5 μg/ml) alone, Con A plus IL-4 (103 U/ml) or Con A plus IL-12 (3.5 ng/ml), in the absence (−) or presence of IL-6 (100 ng/ml) or IL-2 (50 U/ml). After 4 d, cells were exhaustively washed and restimulated (106 cells/ml) with Con A alone (2.5 μg/ml) in the absence of APCs or additional cytokines. Supernatants were harvested 24 h later and analyzed for IL-4 and IFN-γ production by ELISA. (B) Total CD4+ population was isolated from Cyt c TCR transgenic mice, and the naive CD4+ CD45RBhighCD44low subpopulation was purified by cell sorting. Naive CD4+ T cells were then stimulated with Con A alone, Con A plus IL-4, or Con A plus IL-12, and APCs, in the presence or absence of IL-6. After 4 d, cells were exhaustively washed and restimulated (106 cell/ ml) with Con A alone for 24 h before harvesting the supernatants for cytokine measurement. (C) Naive CD4+CD45RBhighCD44low CD4+ T cells isolated from Cyt c TCR transgenic mice were stimulated with Cyt c peptide and APCs, in the presence of medium, IL-6 (100 ng/ml), or IL-4, (103 U/ml). After 4 d, cells were exhaustively washed and restimulated (106 cell/ml) with Cyt c peptide and APCs for 24 h. (D) Total CD4+ T cells from normal B10.BR mice were stimulated with immobilized anti– CD3 mAb (5 μg/ml) and soluble anti–CD28 (1 μg/ml) in the presence of medium (−), IL-6 (100 ng/ml), or IL-4 (103 U/ml) and, after 4 d, they were restimulated with immobilized anti–CD3 mAb. (E) Total CD4+ T cells from normal B10.BR mice were stimulated with Con A and APCs in the presence of medium (−), IL-6 (100 ng/ml) (IL-6), or IL-6 (100 ng/ml) plus anti–IL-4 mAb (10 μg/ml) (IL-6 + anti–IL-4), for 4 d. Cells were then restimulated (106 cells/ml) with Con A alone as described in A.CC BY-NC-SA · PubMed Central
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.
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.CC BY-NC-SA · PubMed Central
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.
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.CC BY-NC-SA · PubMed Central
Figure 4 Schematic model for the differentiation of precursors Th cells (pTh) into effector Th1 and Th2 cells.
Figure 4 Schematic model for the differentiation of precursors Th cells (pTh) into effector Th1 and Th2 cells.CC BY-NC-SA · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 55 references

Research works printed but not linked: 1

  1. Chomczynski, 1987, Single-step method of RNA extraction by acid guanidinium thiocyanate-phenolchloroform, Anal Biochem, 162, 156, 10.1016/0003-2697(87)90021-2 · DOI

Cited by

Sorted by citations

See all 810

Related

Metadata

Authors
Rincón, M., Anguita, J., Nakamura, T., Fikrig, E., & Flavell, R. A.
Affiliations
  • Howard Hughes Medical Institute (US)
  • From the *Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8011; ‡Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-9031; and §Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520-8011
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
1997-02-03
Volume
185
Issue
3
Pages
461-470
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.185.3.461
PMC
PMC2196041
OpenAlex
W2150763544
Cited by
810
References
55
Citations by year
2026: 3 · 2025: 11 · 2024: 14 · 2023: 18 · 2022: 20 · 2021: 23 · 2020: 23 · 2019: 19 · 2018: 19 · 2017: 15 · 2016: 18 · 2015: 16 · 2014: 30 · 2013: 9 · 2012: 25
FWCI
29.64
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p01ai030548-09)
  • National Cancer Institute (CA-65861, R01CA065861)
  • National Institute of Allergy and Infectious Diseases (1-P01-AI30548)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Keywords
interleukin-6, IL-4, CD4+ T cells, Th2 differentiation, Th1 differentiation, antigen-presenting cells, immune regulation
MeSH terms
Animals, Antigen-Presenting Cells, Cell Differentiation, Mice, Inbred C57BL, CD4-Positive T-Lymphocytes, Interleukin-4, Interleukin-6, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review