The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells

Minoru Fujimoto, Mayumi Nakano, Fumitaka Terabe, Hirohisa Kawahata, Tomoharu Ohkawara, Yongmei Han, Barry Ripley, Satoshi Serada, Teppei Nishikawa, Akihiro Kimura, Shintaro Nomura, Tadamitsu Kishimoto, Tetsuji Naka

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

IL-6 is a proinflammatory cytokine and its overproduction is implicated in a variety of inflammatory disorders. Recent in vitro analyses suggest that IL-6 is a key cytokine that determines the balance between Foxp3+ regulatory T cells (Tregs) and Th17 cells. However, it remains unclear whether excessive IL-6 production in vivo alters the development and function of Foxp3+ Tregs. In this study, we analyzed IL-6 transgenic (Tg) mice in which serum IL-6 levels are constitutively elevated. Interestingly, in IL-6 Tg mice, whereas peripheral lymphoid organs were enlarged, and T cells exhibited activated phenotype, Tregs were not reduced but rather increased compared with wild-type mice. In addition, Tregs from Tg mice normally suppressed proliferation of naive T cells in vitro. Furthermore, Tregs cotransferred with naive CD4 T cells into SCID-IL-6 Tg mice inhibited colitis as successfully as those transferred into control SCID mice. These results indicate that overproduction of IL-6 does not inhibit development or function of Foxp3 + Tregs in vivo. However, when naive CD4 T cells alone were transferred, Foxp3+ Tregs retrieved from SCID-IL-6 Tg mice were reduced compared with SCID mice. Moreover, the Helios- subpopulation of Foxp3+ Tregs, recently defined as extrathymic Tregs, was significantly reduced in IL-6 Tg mice compared with wild-type mice. Collectively, these results suggest that IL-6 overproduced in vivo inhibits inducible Treg generation from naive T cells, but does not affect the development and function of natural Tregs.

Original languageEnglish
Pages (from-to)32-40
Number of pages9
JournalJournal of Immunology
Volume186
Issue number1
DOIs
Publication statusPublished - 2011 Jan 1

Fingerprint

Regulatory T-Lymphocytes
Interleukin-6
Transgenic Mice
T-Lymphocytes
SCID Mice
Cytokines
Th17 Cells
Colitis
Phenotype

ASJC Scopus subject areas

  • Immunology

Cite this

Fujimoto, M., Nakano, M., Terabe, F., Kawahata, H., Ohkawara, T., Han, Y., ... Naka, T. (2011). The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells. Journal of Immunology, 186(1), 32-40. https://doi.org/10.4049/jimmunol.0903314

The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells. / Fujimoto, Minoru; Nakano, Mayumi; Terabe, Fumitaka; Kawahata, Hirohisa; Ohkawara, Tomoharu; Han, Yongmei; Ripley, Barry; Serada, Satoshi; Nishikawa, Teppei; Kimura, Akihiro; Nomura, Shintaro; Kishimoto, Tadamitsu; Naka, Tetsuji.

In: Journal of Immunology, Vol. 186, No. 1, 01.01.2011, p. 32-40.

Research output: Contribution to journalArticle

Fujimoto, M, Nakano, M, Terabe, F, Kawahata, H, Ohkawara, T, Han, Y, Ripley, B, Serada, S, Nishikawa, T, Kimura, A, Nomura, S, Kishimoto, T & Naka, T 2011, 'The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells', Journal of Immunology, vol. 186, no. 1, pp. 32-40. https://doi.org/10.4049/jimmunol.0903314
Fujimoto, Minoru ; Nakano, Mayumi ; Terabe, Fumitaka ; Kawahata, Hirohisa ; Ohkawara, Tomoharu ; Han, Yongmei ; Ripley, Barry ; Serada, Satoshi ; Nishikawa, Teppei ; Kimura, Akihiro ; Nomura, Shintaro ; Kishimoto, Tadamitsu ; Naka, Tetsuji. / The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells. In: Journal of Immunology. 2011 ; Vol. 186, No. 1. pp. 32-40.
@article{467336d484ba4a09b384130259d08b45,
title = "The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells",
abstract = "IL-6 is a proinflammatory cytokine and its overproduction is implicated in a variety of inflammatory disorders. Recent in vitro analyses suggest that IL-6 is a key cytokine that determines the balance between Foxp3+ regulatory T cells (Tregs) and Th17 cells. However, it remains unclear whether excessive IL-6 production in vivo alters the development and function of Foxp3+ Tregs. In this study, we analyzed IL-6 transgenic (Tg) mice in which serum IL-6 levels are constitutively elevated. Interestingly, in IL-6 Tg mice, whereas peripheral lymphoid organs were enlarged, and T cells exhibited activated phenotype, Tregs were not reduced but rather increased compared with wild-type mice. In addition, Tregs from Tg mice normally suppressed proliferation of naive T cells in vitro. Furthermore, Tregs cotransferred with naive CD4 T cells into SCID-IL-6 Tg mice inhibited colitis as successfully as those transferred into control SCID mice. These results indicate that overproduction of IL-6 does not inhibit development or function of Foxp3 + Tregs in vivo. However, when naive CD4 T cells alone were transferred, Foxp3+ Tregs retrieved from SCID-IL-6 Tg mice were reduced compared with SCID mice. Moreover, the Helios- subpopulation of Foxp3+ Tregs, recently defined as extrathymic Tregs, was significantly reduced in IL-6 Tg mice compared with wild-type mice. Collectively, these results suggest that IL-6 overproduced in vivo inhibits inducible Treg generation from naive T cells, but does not affect the development and function of natural Tregs.",
author = "Minoru Fujimoto and Mayumi Nakano and Fumitaka Terabe and Hirohisa Kawahata and Tomoharu Ohkawara and Yongmei Han and Barry Ripley and Satoshi Serada and Teppei Nishikawa and Akihiro Kimura and Shintaro Nomura and Tadamitsu Kishimoto and Tetsuji Naka",
year = "2011",
month = "1",
day = "1",
doi = "10.4049/jimmunol.0903314",
language = "English",
volume = "186",
pages = "32--40",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

TY - JOUR

T1 - The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells

AU - Fujimoto, Minoru

AU - Nakano, Mayumi

AU - Terabe, Fumitaka

AU - Kawahata, Hirohisa

AU - Ohkawara, Tomoharu

AU - Han, Yongmei

AU - Ripley, Barry

AU - Serada, Satoshi

AU - Nishikawa, Teppei

AU - Kimura, Akihiro

AU - Nomura, Shintaro

AU - Kishimoto, Tadamitsu

AU - Naka, Tetsuji

PY - 2011/1/1

Y1 - 2011/1/1

N2 - IL-6 is a proinflammatory cytokine and its overproduction is implicated in a variety of inflammatory disorders. Recent in vitro analyses suggest that IL-6 is a key cytokine that determines the balance between Foxp3+ regulatory T cells (Tregs) and Th17 cells. However, it remains unclear whether excessive IL-6 production in vivo alters the development and function of Foxp3+ Tregs. In this study, we analyzed IL-6 transgenic (Tg) mice in which serum IL-6 levels are constitutively elevated. Interestingly, in IL-6 Tg mice, whereas peripheral lymphoid organs were enlarged, and T cells exhibited activated phenotype, Tregs were not reduced but rather increased compared with wild-type mice. In addition, Tregs from Tg mice normally suppressed proliferation of naive T cells in vitro. Furthermore, Tregs cotransferred with naive CD4 T cells into SCID-IL-6 Tg mice inhibited colitis as successfully as those transferred into control SCID mice. These results indicate that overproduction of IL-6 does not inhibit development or function of Foxp3 + Tregs in vivo. However, when naive CD4 T cells alone were transferred, Foxp3+ Tregs retrieved from SCID-IL-6 Tg mice were reduced compared with SCID mice. Moreover, the Helios- subpopulation of Foxp3+ Tregs, recently defined as extrathymic Tregs, was significantly reduced in IL-6 Tg mice compared with wild-type mice. Collectively, these results suggest that IL-6 overproduced in vivo inhibits inducible Treg generation from naive T cells, but does not affect the development and function of natural Tregs.

AB - IL-6 is a proinflammatory cytokine and its overproduction is implicated in a variety of inflammatory disorders. Recent in vitro analyses suggest that IL-6 is a key cytokine that determines the balance between Foxp3+ regulatory T cells (Tregs) and Th17 cells. However, it remains unclear whether excessive IL-6 production in vivo alters the development and function of Foxp3+ Tregs. In this study, we analyzed IL-6 transgenic (Tg) mice in which serum IL-6 levels are constitutively elevated. Interestingly, in IL-6 Tg mice, whereas peripheral lymphoid organs were enlarged, and T cells exhibited activated phenotype, Tregs were not reduced but rather increased compared with wild-type mice. In addition, Tregs from Tg mice normally suppressed proliferation of naive T cells in vitro. Furthermore, Tregs cotransferred with naive CD4 T cells into SCID-IL-6 Tg mice inhibited colitis as successfully as those transferred into control SCID mice. These results indicate that overproduction of IL-6 does not inhibit development or function of Foxp3 + Tregs in vivo. However, when naive CD4 T cells alone were transferred, Foxp3+ Tregs retrieved from SCID-IL-6 Tg mice were reduced compared with SCID mice. Moreover, the Helios- subpopulation of Foxp3+ Tregs, recently defined as extrathymic Tregs, was significantly reduced in IL-6 Tg mice compared with wild-type mice. Collectively, these results suggest that IL-6 overproduced in vivo inhibits inducible Treg generation from naive T cells, but does not affect the development and function of natural Tregs.

UR - http://www.scopus.com/inward/record.url?scp=79251543298&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79251543298&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.0903314

DO - 10.4049/jimmunol.0903314

M3 - Article

C2 - 21106853

AN - SCOPUS:79251543298

VL - 186

SP - 32

EP - 40

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 1

ER -