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Homeostatic Proliferation as an Isolated Variable Reverses CD8⁺ T Cell Anergy and Promotes Tumor Rejection¹

Department of Pathology and Department of Medicine, University of Chicago, Chicago, IL 60637

Although recent work has suggested that lymphopenia-induced homeostatic proliferation may improve T cell-mediated tumor rejection, there is little direct evidence isolating homeostatic proliferation as an experimental variable, and the mechanism by which improved antitumor immunity occurs via homeostatic proliferation is poorly understood. An adoptive transfer model was developed in which tumor-specific 2C/RAG2^–/– TCR transgenic CD8⁺ T cells were introduced either into the lymphopenic environment of RAG2^–/– mice or into P14/RAG2^–/– mice containing an irrelevant CD8⁺ TCR transgenic population. RAG2^–/–, but not P14/RAG2^–/– recipients supported homeostatic proliferation of transferred T cells as well as tumor rejection. Despite absence of tumor rejection in P14/RAG2^–/– recipients, 2C cells did become activated, as reflected by CFSE dilution and CD44 up-regulation. However, these cells showed poor IFN- and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide Ag. To determine whether homeostatic proliferation could uncouple T cell anergy, anergic 2C cells were transferred into RAG^–/– recipients, which resulted in vigorous homeostatic proliferation, recovery of IL-2 production, and acquisition of the ability to reject tumors. Taken together, our data suggest that a major mechanism by which homeostatic proliferation supports tumor rejection is by maintaining and/or re-establishing T cell responsiveness.

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 National Institutes of Health Grant P01CA97296 and a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research. I.E.B. received support from Pediatric Growth and Development Training Grant HD007009. C.B. was supported by Deutsche Akademie der Naturforscher Leopoldina Grant BMBF-LPD 9901/8-35 with funds from the Bundesministerium fuer Bildung und Forschung and by Deutsche Forschungsgemeinschaft Grant BL 786/1-1.

² Address correspondence and reprint requests to Dr. Thomas F. Gajewski, University of Chicago, 5841 South Maryland Avenue, MC2115, Chicago, IL 60637. E-mail address: tgajewsk{at}medicine.bsd.uchicago.edu

³ Abbreviations used in this paper: TIL, tumor-infiltrating lymphocyte; Tg, transgenic.

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