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.
authors.affiliation: Department of Immunology and Genetic Medicine, Graduate school of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Chikuma
authors.forename: Seigo
authors.initials: S
authors.lastname: Terawaki
authors.forename: Tamon
authors.initials: T
authors.lastname: Hayashi
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Nabeshima
authors.forename: Takao
authors.initials: T
authors.lastname: Yoshida
authors.forename: Shiro
authors.initials: S
authors.lastname: Shibayama
authors.forename: Taku
authors.initials: T
authors.lastname: Okazaki
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017635:Clonal Anergy; D005786:Gene Expression Regulation / Q000276:immunology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor
chemical_list: D000941:Antigens; D000943:Antigens, Differentiation; D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor