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

J Immunol. 2009 Jun 1;182(11):6682-9. doi: 10.4049/jimmunol.0900080.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / immunology
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Clonal Anergy*
  • Gene Expression Regulation / immunology
  • Interleukin-2 / antagonists & inhibitors*
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / genetics
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Programmed Cell Death 1 Receptor


  • Antigens
  • Antigens, Differentiation
  • Interleukin-2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor