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 Zhao, B. Articles by Song, J. Search for Related Content PubMed PubMed Citation Articles by Zhao, B. Articles by Song, J.

Cooperation between Molecular Targets of Costimulation in Promoting T Cell Persistence and Tumor Regression¹

Baohua Zhao^2,, Aihua Song^2,, Rizwanul Haque^*, Fengyang Lei^*, Lauren Weiler^*, Xiaofang Xiong^*, Yuzhang Wu, Michael Croft^3, and Jianxun Song^3,*,

^* Department of Microbiology and Immunology and Pennsylvania State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033; College of Life Science, Hebei Normal University, Shijiazhuang, China; Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037; and Institute of Immunology, The Third Military Medical University, Chongqing, China

Costimulation regulates multiple cellular processes of T cells inducing proliferation, expansion, and survival. The molecular targets of costimulation might then be useful to augment T cell activities. Two defined targets of costimulatory signals in primary T cells are the anti-apoptotic bcl-2 family molecule Bcl-x_L, and survivin, an inhibitor of apoptosis family member that might regulate both cell division and survival. However, the relative importance of, and relationship between, these molecules in primary T cells is not clear. To understand whether they have overlapping or cooperative functions, we used retrovirus-mediated transduction to introduce Bcl-x_L and survivin separately, or together linked by a 2A picornavirus self-cleaving peptide, into Ag-responding CD8⁺ T cells. We found that CD8⁺ effector T cells expressing both Bcl-x_L and survivin strongly expanded at an early stage and had a long-term survival advantage over cells transduced with either molecule alone. In vivo, with response to tumor-expressed Ag following adoptive T cell transfer, Ag-reactive CD8⁺ T cells expressing both Bcl-x_L and survivin displayed greatly enhanced tumor protective activity compared with CD8⁺ T cells expressing either molecule introduced separately. These results indicate that Bcl-x_L and survivin can critically contribute in a cooperative, nonredundant manner to augment the accumulation and persistence of CD8⁺ T cells following encounter with Ag. The data provide new insights into why costimulatory signals might need to be sustained over time and suggest a potential novel approach to augment cellular immunotherapy for cancer.

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 from the Pennsylvania Department of Health and the St. Baldrick’s Foundation (to J.S.), and National Institutes of Health Grants CA91837 and AI49453 (to M.C.).

² These authors contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jianxun Song, 500 University Drive, Hershey, PA 17033 or Dr. Michael Croft, 9420 Athena Circle, La Jolla, CA 92037. E-mail addresses: jus35{at}psu.edu or mick{at}liai.org

⁴ Abbreviations used in this paper: TNFR, TNF receptor; FMDV, foot-and-mouth disease virus; Rg, retrogenic; LN, lymph node; CTL, cytotoxic T lymphocyte.