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Blood, 15 December 2003, Vol. 102, No. 13, pp. 4320-4325. Prepublished online as a Blood First Edition Paper on August 28, 2003; DOI 10.1182/blood-2003-04-1255. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-04-1255v1 102/13/4320    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 Nguyen, P. Articles by Geiger, T. L. Search for Related Content PubMed PubMed Citation Articles by Nguyen, P. Articles by Geiger, T. L. Related Collections Immunobiology Immunotherapy Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Identification of a murine CD28 dileucine motif that suppresses single-chain chimeric T-cell receptor expression and function Phuong Nguyen, Ioana Moisini, and Terrence L. Geiger From the Department of Pathology, St Jude Children's Research Hospital, Memphis, TN; and Department of Pathology, University of Tennessee School of Medicine, Memphis. Recent preclinical and clinical trials have demonstrated the therapeutic potential of T lymphocytes redirected with genetically engineered T-cell receptor (TCR) surrogates against infected, cancerous, or autoreactive cells. These surrogate TCRs link a ligand-recognition domain to signaling regions from the TCR. We previously compared the function of surrogate TCRs that include TCR or TCR and CD28 signaling regions. We found that primary murine T cells modified to specifically target Kb-restricted CD8+ T cells using either Kb- or Kb-CD28- receptors had similar functional activities, although the CD28- receptor showed a 2-fold to 4-fold decreased expression. We have now identified a previously unrecognized dileucine motif in the murine CD28 signaling domain that accounts for this reduced expression. Inactivation of this motif increased chimeric receptor surface expression 2- to 5-fold. T cells expressing the dileucine-mutated CD28- chimeric receptor demonstrated enhanced proliferation, cytokine production, and cytolytic activities. Further, cells expressing this dileucine-mutated receptor were highly effective in eliminating antigen-specific CD8+ T lymphocytes in vivo. These results therefore identify a critical motif limiting the function of receptor-modified T lymphocytes, demonstrate that inactivation of this motif enhances chimeric receptor function, and illustrate a potential novel application of receptor-modified T lymphocytes in the induction of immune tolerance. (Blood. 2003;102:4320-4325) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. M. Kowolik, M. S. Topp, S. Gonzalez, T. Pfeiffer, S. Olivares, N. Gonzalez, D. D. Smith, S. J. Forman, M. C. Jensen, and L. J.N. Cooper CD28 Costimulation Provided through a CD19-Specific Chimeric Antigen Receptor Enhances In vivo Persistence and Antitumor Efficacy of Adoptively Transferred T Cells. Cancer Res., November 15, 2006; 66(22): 10995 - 11004. [Abstract] [Full Text] [PDF]

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