Down-regulation of ICOS ligand by interaction with ICOS functions as a regulatory mechanism for immune responses

Masashi Watanabe, Yuri Takagi, Motoko Kotani, Yasushi Hara, Ayako Inamine, Katsuhiko Hayashi, Shuhei Ogawa, Kei Takeda, Kazunari Tanabe, Ryo Abe

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Although it is well-known that the ICOS-ICOS ligand (ICOSL) costimulatory pathway is important for many immune responses, recent accumulated evidence suggests that dysregulation of this pathway may lead to and/or exaggerate autoimmune responses. ICOS is induced on the cell surface after T cell activation. Similarly, ICOSL is up-regulated on APCs by several mitogenic stimuli. However, the mechanism regulating expression of the ICOS-ICOSL pair, and the significance of controlling their expression for an appropriate immune response, is largely unknown. To gain a better understanding of the importance of fine control of the ICOS-ICOSL costimulatory pathway, we generated ICOS-transgenic (Tg) mice that have high constitutive expression of ICOS in all T cells. Using ICOS-Tg mice, we studied whether in vivo immune responses were affected. Unexpectedly, we first found that ICOS-Tg mice exhibited a phenotype resembling ICOS-deficient mice in their Ag-specific Ab response, such as a defect in class switch recombination. Further examination revealed that ICOSL expression of APCs was significantly suppressed in ICOS-Tg mice. Interestingly, suppression of ICOSL was induced by interaction of ICOSL with ICOS, and it seemed to be regulated at the posttranscriptional level. The suppressive effect of the ICOS-ICOSL interaction overcame the positive effect of CD40 or B cell activation factor of the TNF family (BAFF) stimulation on ICOSL expression. Together, our studies demonstrate a novel mechanism for the regulation of ICOSL expression in vivo and suggest that the ICOS costimulatory pathway is subject to negative feedback regulation by ICOSL down-regulation in response to ICOS expression. The Journal of Immunology, 2008, 180:

Original languageEnglish
Pages (from-to)5222-5234
Number of pages13
JournalJournal of Immunology
Volume180
Issue number8
DOIs
Publication statusPublished - Apr 15 2008

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Down-Regulation
Ligands
Transgenic Mice
T-Lymphocytes
Allergy and Immunology
Autoimmunity
Genetic Recombination
B-Lymphocytes
Phenotype

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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Down-regulation of ICOS ligand by interaction with ICOS functions as a regulatory mechanism for immune responses. / Watanabe, Masashi; Takagi, Yuri; Kotani, Motoko; Hara, Yasushi; Inamine, Ayako; Hayashi, Katsuhiko; Ogawa, Shuhei; Takeda, Kei; Tanabe, Kazunari; Abe, Ryo.

In: Journal of Immunology, Vol. 180, No. 8, 15.04.2008, p. 5222-5234.

Research output: Contribution to journalArticle

Watanabe, M, Takagi, Y, Kotani, M, Hara, Y, Inamine, A, Hayashi, K, Ogawa, S, Takeda, K, Tanabe, K & Abe, R 2008, 'Down-regulation of ICOS ligand by interaction with ICOS functions as a regulatory mechanism for immune responses', Journal of Immunology, vol. 180, no. 8, pp. 5222-5234. https://doi.org/10.4049/jimmunol.180.8.5222
Watanabe, Masashi ; Takagi, Yuri ; Kotani, Motoko ; Hara, Yasushi ; Inamine, Ayako ; Hayashi, Katsuhiko ; Ogawa, Shuhei ; Takeda, Kei ; Tanabe, Kazunari ; Abe, Ryo. / Down-regulation of ICOS ligand by interaction with ICOS functions as a regulatory mechanism for immune responses. In: Journal of Immunology. 2008 ; Vol. 180, No. 8. pp. 5222-5234.
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AB - Although it is well-known that the ICOS-ICOS ligand (ICOSL) costimulatory pathway is important for many immune responses, recent accumulated evidence suggests that dysregulation of this pathway may lead to and/or exaggerate autoimmune responses. ICOS is induced on the cell surface after T cell activation. Similarly, ICOSL is up-regulated on APCs by several mitogenic stimuli. However, the mechanism regulating expression of the ICOS-ICOSL pair, and the significance of controlling their expression for an appropriate immune response, is largely unknown. To gain a better understanding of the importance of fine control of the ICOS-ICOSL costimulatory pathway, we generated ICOS-transgenic (Tg) mice that have high constitutive expression of ICOS in all T cells. Using ICOS-Tg mice, we studied whether in vivo immune responses were affected. Unexpectedly, we first found that ICOS-Tg mice exhibited a phenotype resembling ICOS-deficient mice in their Ag-specific Ab response, such as a defect in class switch recombination. Further examination revealed that ICOSL expression of APCs was significantly suppressed in ICOS-Tg mice. Interestingly, suppression of ICOSL was induced by interaction of ICOSL with ICOS, and it seemed to be regulated at the posttranscriptional level. The suppressive effect of the ICOS-ICOSL interaction overcame the positive effect of CD40 or B cell activation factor of the TNF family (BAFF) stimulation on ICOSL expression. Together, our studies demonstrate a novel mechanism for the regulation of ICOSL expression in vivo and suggest that the ICOS costimulatory pathway is subject to negative feedback regulation by ICOSL down-regulation in response to ICOS expression. The Journal of Immunology, 2008, 180:

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