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Blood, 1 December 2006, Vol. 108, No. 12, pp. 3818-3823. Prepublished online as a Blood First Edition Paper on August 1, 2006; DOI 10.1182/blood-2006-07-034066. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-07-034066v1 108/12/3818    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gattinoni, L. Articles by Restifo, N. P. Search for Related Content PubMed PubMed Citation Articles by Gattinoni, L. Articles by Restifo, N. P. Related Collections Immunobiology Immunotherapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent Luca Gattinoni, Anju Ranganathan, Deborah R. Surman, Douglas C. Palmer, Paul A. Antony, Marc R. Theoret, David M. Heimann, Steven A. Rosenberg, and Nicholas P. Restifo From the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; and the Howard Hughes Medical Institute–National Institutes of Health Research Scholars Program, Bethesda, MD. Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) maintains peripheral tolerance by suppressing T-cell activation and proliferation but its precise role in vivo remains unclear. We sought to elucidate the impact of CTLA-4 expression on self/tumor-reactive CD8+ T cells by using the glycoprotein (gp) 100–specific T-cell receptor (TCR) transgenic mouse, pmel-1. pmel-1 CLTA-4–/– mice developed profound, accelerated autoimmune vitiligo. This enhanced autoimmunity was associated with a small but highly activated CD8+ T-cell population and large numbers of CD4+ T cells not expressing the transgenic TCR. Adoptive transfer of pmel-1 CLTA-4–/– CD8+ T cells did not mediate superior antitumor immunity in the settings of either large established tumors or tumor challenge, suggesting that the mere absence of CTLA-4–mediated inhibition on CD8+ T cells did not directly promote enhancement of their effector functions. Removal of CD4+ T cells by crossing the pmel-1 CLTA-4–/– mouse onto a Rag-1–/– background resulted in the complete abrogation of CD8+ T-cell activation and autoimmune manifestations. The effects of CD4+ CLTA-4–/– T cells were dependent on the absence of CTLA-4 on CD8+ T cells. These results indicated that CD8+ CLTA-4–/– T-cell–mediated autoimmunity and tumor immunity required CD4+ T cells in which the function was dysregulated by the absence of CTLA-4–mediated negative costimulation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. King, J. Waxman, and H. Stauss Advances in tumour immunotherapy QJM, May 13, 2008; (2008) hcn050v1. [Abstract] [Full Text] [PDF] S. G. Downey, J. A. Klapper, F. O. Smith, J. C. Yang, R. M. Sherry, R. E. Royal, U. S. Kammula, M. S. Hughes, T. E. Allen, C. L. Levy, et al. Prognostic Factors Related to Clinical Response in Patients with Metastatic Melanoma Treated by CTL-Associated Antigen-4 Blockade Clin. Cancer Res., November 15, 2007; 13(22): 6681 - 6688. [Abstract] [Full Text] [PDF]

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