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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 3, 2005 Accepted July 20, 2006 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* National Cancer Institute, NIH, Bethesda, MD, USA National Cancer Institute and Howard Hughes Medical Institute-National Institutes of Health Research National Cancer Institute and Howard Hughes Medical Institute-National * Corresponding author; email: restifo{at}nih.gov. 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 gp100-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 of the absence of CTLA-4 on CD8+ T cells. These results indicated that CD8+ CLTA-4-/- T cell- mediated auto- and tumor-immunity required CD4+ T cells whose 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: A. Ribas, B. Comin-Anduix, B. Chmielowski, J. Jalil, P. de la Rocha, T. A. McCannel, M. T. Ochoa, E. Seja, A. Villanueva, D. K. Oseguera, et al. Dendritic Cell Vaccination Combined with CTLA4 Blockade in Patients with Metastatic Melanoma Clin. Cancer Res., October 1, 2009; 15(19): 6267 - 6276. [Abstract] [Full Text] [PDF] J. King, J. Waxman, and H. Stauss Advances in tumour immunotherapy QJM, September 1, 2008; 101(9): 675 - 683. [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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