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Tumor-Specific CD4⁺ T Cells Render the Tumor Environment Permissive for Infiltration by Low-Avidity CD8⁺ T Cells¹

Department of Immunology, Scripps Research Institute, La Jolla, CA 92037

CD4⁺ T cells enhance tumor destruction by CD8⁺ T cells. One benefit that underlies CD4⁺ T cell help is enhanced clonal expansion of newly activated CD8⁺ cells. In addition, tumor-specific CD4⁺ help is also associated with the accumulation of greater numbers of CD8⁺ T cells within the tumor. Whether this too is attributable to the effects of help delivered to the CD8⁺ cells during priming within secondary lymphoid tissues, or alternatively is due to the action of CD4⁺ cells within the tumor environment has not been examined. In this study, we have evaluated separately the benefits of CD4⁺ T cell help accrued during priming of tumor-specific CD8⁺ T cells with a vaccine, as opposed to the benefits delivered by the presence of cognate CD4⁺ cells within the tumor. The presence of CD4⁺ T cell help during priming increased clonal expansion of tumor-specific CD8⁺ T cells in secondary lymphoid tissue; however, CD8⁺ T cells that have low avidity for tumor Ag were inefficient in tumor invasion. CD4⁺ T cells that recognized tumor Ag were required to facilitate accumulation of CD8⁺ T cells within the tumor and enhance tumor lysis during the acute phase of the response. These experiments highlight the ability of tumor-specific CD4⁺ T cells to render the tumor microenvironment receptive for CD8⁺ T cell immunotherapy, by facilitating the accumulation of all activated CD8⁺ T cells, including low-avidity tumor-specific and noncognate 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 Grant R01 CA57855 from National Institutes of Health. S.B.J.W. was funded by a fellowship from the National University of Singapore. R.B. was funded by a Netherlands Organization for Scientific Research Rubicon Grant from The Netherlands.

² Address correspondence and reprint requests to Dr. Linda A. Sherman, Department of Immunology, The Scripps Research Institute, IMM-15, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: lsherman{at}scripps.edu

³ Abbreviations used in this paper: DC, dendritic cell; HA, hemagglutinin; ORF, open reading frame; RIP, rat insulin promotor; vacHA, vaccinia virus expressing the HA protein; vacOVA-HA2, vaccinia OVA-HA2; vacSFE, vaccinia SFE.

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The JI 2008 180: 2721-2722. [Full Text]