HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Chikuma, S. Articles by Honjo, T. Search for Related Content PubMed PubMed Citation Articles by Chikuma, S. Articles by Honjo, T. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Substance via MeSH

PD-1-Mediated Suppression of IL-2 Production Induces CD8⁺ T Cell Anergy In Vivo¹

Shunsuke Chikuma^*, Seigo Terawaki^*, Tamon Hayashi, Ryusuke Nabeshima, Takao Yoshida, Shiro Shibayama, Taku Okazaki^*, and Tasuku Honjo^2,*

^* Department of Immunology and Genetic Medicine, Graduate school of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan; Exploratory Research Laboratories, Ono Pharmaceutical Company, Tsukuba, Ibaraki, Japan; and Division of Immune Regulation, Institute for Genome Research, University of Tokushima, Tokushima, Japan

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, Culture and Technology of Japan (19790356 to S.C., 17047024 and 19689012 to T.O.) and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (to T.H.).

² Address correspondence and reprint requests to Tasuku Honjo, Department of Immunology, and Genetic Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan. E-mail address: honjo{at}mfour.med.kyoto-u.ac.jp

³ Abbreviations used in this paper: Tg, transgenic; DC, dendritic cell; CAG-GFP, chicken β-actin promoter driven enhanced GFP Tg mice; PD-1, programmed cell death-1; LN, lymph node.