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Induction of Antitumor Immune Response by Homeostatic Proliferation and CD28 Signaling

Toshihiro Suzuki^*, Shuhei Ogawa^*, Kazunari Tanabe, Hideaki Tahara, Ryo Abe^* and Hidehiro Kishimoto^1,*

^* Division of Immunobiology, Research Institute for Biological Science, Tokyo University of Science, Noda City; Department of Urology, Tokyo Women’s Medical University, Tokyo, Japan; Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Inducing lymphopenia before adoptive cell transfer can improve the antitumor effect of donor immune cells. It was recently reported that lymphopenic conditions can initiate the differentiation of naive T cells into effector cells. Although T cells require a specific "strong" signal via TCR as well as costimulatory signals during Ag-driven differentiation, there has been little evidence to suggest any requirement for costimulatory signaling for the differentiation of naive T cells in a lymphopenic host. In this study, we demonstrate that naive CD8⁺ T cells are indispensable for induction of antitumor effect, and, in addition to Ag-driven differentiation, CD28 signaling is essential for the differentiation of naive CD8⁺ T cells into functional effector CTLs during homeostatic proliferation (HP). The systemic administration of IL-2 did not restore the antitumor effect induced by HP in the absence of CD28 signaling. These results suggest that homeostatic cytokines enable CD8⁺ T cells to expand and survive, and that TCR and the CD28 signal initiate the differentiation of effector functions. A deeper understanding of the mechanisms underlying enhanced induction of the antitumor immune response with accompanying HP may allow us to more precisely induce enhanced immunity with costimulation signaling and the administration of common -chain cytokines.

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 Address correspondence and reprint requests to Dr. Hidehiro Kishimoto, Division of Immunobiology, Research Institute for Biological Science, Tokyo University of Science, 2669 Yamazaki, Noda City, Chiba, 278-0022, Japan. E-mail address: hidek{at}rs.noda.tus.ac.jp

² Abbreviations used in this paper: TAA, tumor-associated Ag; HP, homeostatic proliferation; i.d., intradermal(ly); T_CM, central memory T; T_CMP, central memory phenotype T; T_EM, effector memory T; T_EMP, effector memory phenotype T.

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The JI 2008 180: 4349-4350. [Full Text]