PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo

Shunsuke Chikuma, Seigo Terawaki, Tamon Hayashi, Ryusuke Nabeshima, Takao Yoshida, Shiro Shibayama, Taku Okazaki, Tasuku Honjo

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Accumulating evidence suggests that PD-1, an immuno-inhibitory receptor expressed on activated T cells, regulates peripheral T cell tolerance. In particular, PD-1 is involved in the induction and/or maintenance of T cells' intrinsic unresponsiveness to previously encountered Ags, although the mechanism is yet to be determined. We used a simple experimental model to dissect the mechanism for anergy establishment, in which 2C TCR transgenic rag2 -/- PD-1-/- mice were anergized by a single injection of a cognate peptide. Interestingly, 2C rag2-/- PD-1+/+ mice were totally resistant to anergy induction by the same treatment; thus, PD-1 was responsible for anergy induction. Furthermore, PD-1 expression was induced within 24 h of the initial Ag exposure. The establishment of anergy was associated with a marked down-regulation of IL-2 from the CD8+ T cells. In fact, IL-2 blockade resulted in anergy even in 2C rag2 -/-PD-1-/- T cells. Furthermore, the complementation of the IL-2 signal in 2C rag2-/- PD-1+/+ mice reversed the anergy induction. We propose that CD8+ T cell anergy is induced by a reduction of cell-autonomous IL-2 synthesis, which is caused by the quick expression of PD-1 in response to Ag stimulation and the subsequent stimulation of this receptor by its ligands on surrounding cells.

Original languageEnglish
Pages (from-to)6682-6689
Number of pages8
JournalJournal of Immunology
Volume182
Issue number11
DOIs
Publication statusPublished - 2009 Jun 1
Externally publishedYes

Fingerprint

Interleukin-2
T-Lymphocytes
Theoretical Models
Down-Regulation
Maintenance
Ligands
Peptides
Injections

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Chikuma, S., Terawaki, S., Hayashi, T., Nabeshima, R., Yoshida, T., Shibayama, S., ... Honjo, T. (2009). PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. Journal of Immunology, 182(11), 6682-6689. https://doi.org/10.4049/jimmunol.0900080

PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. / Chikuma, Shunsuke; Terawaki, Seigo; Hayashi, Tamon; Nabeshima, Ryusuke; Yoshida, Takao; Shibayama, Shiro; Okazaki, Taku; Honjo, Tasuku.

In: Journal of Immunology, Vol. 182, No. 11, 01.06.2009, p. 6682-6689.

Research output: Contribution to journalArticle

Chikuma, S, Terawaki, S, Hayashi, T, Nabeshima, R, Yoshida, T, Shibayama, S, Okazaki, T & Honjo, T 2009, 'PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo', Journal of Immunology, vol. 182, no. 11, pp. 6682-6689. https://doi.org/10.4049/jimmunol.0900080
Chikuma S, Terawaki S, Hayashi T, Nabeshima R, Yoshida T, Shibayama S et al. PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. Journal of Immunology. 2009 Jun 1;182(11):6682-6689. https://doi.org/10.4049/jimmunol.0900080
Chikuma, Shunsuke ; Terawaki, Seigo ; Hayashi, Tamon ; Nabeshima, Ryusuke ; Yoshida, Takao ; Shibayama, Shiro ; Okazaki, Taku ; Honjo, Tasuku. / PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. In: Journal of Immunology. 2009 ; Vol. 182, No. 11. pp. 6682-6689.
@article{ded0387e4c4a43e5bd807c473cdbb5e8,
title = "PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo",
abstract = "Accumulating evidence suggests that PD-1, an immuno-inhibitory receptor expressed on activated T cells, regulates peripheral T cell tolerance. In particular, PD-1 is involved in the induction and/or maintenance of T cells' intrinsic unresponsiveness to previously encountered Ags, although the mechanism is yet to be determined. We used a simple experimental model to dissect the mechanism for anergy establishment, in which 2C TCR transgenic rag2 -/- PD-1-/- mice were anergized by a single injection of a cognate peptide. Interestingly, 2C rag2-/- PD-1+/+ mice were totally resistant to anergy induction by the same treatment; thus, PD-1 was responsible for anergy induction. Furthermore, PD-1 expression was induced within 24 h of the initial Ag exposure. The establishment of anergy was associated with a marked down-regulation of IL-2 from the CD8+ T cells. In fact, IL-2 blockade resulted in anergy even in 2C rag2 -/-PD-1-/- T cells. Furthermore, the complementation of the IL-2 signal in 2C rag2-/- PD-1+/+ mice reversed the anergy induction. We propose that CD8+ T cell anergy is induced by a reduction of cell-autonomous IL-2 synthesis, which is caused by the quick expression of PD-1 in response to Ag stimulation and the subsequent stimulation of this receptor by its ligands on surrounding cells.",
author = "Shunsuke Chikuma and Seigo Terawaki and Tamon Hayashi and Ryusuke Nabeshima and Takao Yoshida and Shiro Shibayama and Taku Okazaki and Tasuku Honjo",
year = "2009",
month = "6",
day = "1",
doi = "10.4049/jimmunol.0900080",
language = "English",
volume = "182",
pages = "6682--6689",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "11",

}

TY - JOUR

T1 - PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo

AU - Chikuma, Shunsuke

AU - Terawaki, Seigo

AU - Hayashi, Tamon

AU - Nabeshima, Ryusuke

AU - Yoshida, Takao

AU - Shibayama, Shiro

AU - Okazaki, Taku

AU - Honjo, Tasuku

PY - 2009/6/1

Y1 - 2009/6/1

N2 - Accumulating evidence suggests that PD-1, an immuno-inhibitory receptor expressed on activated T cells, regulates peripheral T cell tolerance. In particular, PD-1 is involved in the induction and/or maintenance of T cells' intrinsic unresponsiveness to previously encountered Ags, although the mechanism is yet to be determined. We used a simple experimental model to dissect the mechanism for anergy establishment, in which 2C TCR transgenic rag2 -/- PD-1-/- mice were anergized by a single injection of a cognate peptide. Interestingly, 2C rag2-/- PD-1+/+ mice were totally resistant to anergy induction by the same treatment; thus, PD-1 was responsible for anergy induction. Furthermore, PD-1 expression was induced within 24 h of the initial Ag exposure. The establishment of anergy was associated with a marked down-regulation of IL-2 from the CD8+ T cells. In fact, IL-2 blockade resulted in anergy even in 2C rag2 -/-PD-1-/- T cells. Furthermore, the complementation of the IL-2 signal in 2C rag2-/- PD-1+/+ mice reversed the anergy induction. We propose that CD8+ T cell anergy is induced by a reduction of cell-autonomous IL-2 synthesis, which is caused by the quick expression of PD-1 in response to Ag stimulation and the subsequent stimulation of this receptor by its ligands on surrounding cells.

AB - Accumulating evidence suggests that PD-1, an immuno-inhibitory receptor expressed on activated T cells, regulates peripheral T cell tolerance. In particular, PD-1 is involved in the induction and/or maintenance of T cells' intrinsic unresponsiveness to previously encountered Ags, although the mechanism is yet to be determined. We used a simple experimental model to dissect the mechanism for anergy establishment, in which 2C TCR transgenic rag2 -/- PD-1-/- mice were anergized by a single injection of a cognate peptide. Interestingly, 2C rag2-/- PD-1+/+ mice were totally resistant to anergy induction by the same treatment; thus, PD-1 was responsible for anergy induction. Furthermore, PD-1 expression was induced within 24 h of the initial Ag exposure. The establishment of anergy was associated with a marked down-regulation of IL-2 from the CD8+ T cells. In fact, IL-2 blockade resulted in anergy even in 2C rag2 -/-PD-1-/- T cells. Furthermore, the complementation of the IL-2 signal in 2C rag2-/- PD-1+/+ mice reversed the anergy induction. We propose that CD8+ T cell anergy is induced by a reduction of cell-autonomous IL-2 synthesis, which is caused by the quick expression of PD-1 in response to Ag stimulation and the subsequent stimulation of this receptor by its ligands on surrounding cells.

UR - http://www.scopus.com/inward/record.url?scp=67449132078&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67449132078&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.0900080

DO - 10.4049/jimmunol.0900080

M3 - Article

VL - 182

SP - 6682

EP - 6689

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 11

ER -