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

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134 Citations (Scopus)


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
Issue number11
Publication statusPublished - 2009 Jun 1
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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