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Definition of Key Variables for the Induction of Optimal NY-ESO-1-Specific T Cells in HLA Transgene Mice

Definition of Key Variables for the Induction of Optimal NY-ESO-1-Specific T Cells in HLA Transgene Mice

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JOHANNSEN, Alexandre, Raphael GENOLET, Daniel F. LEGLER, Sanjiv A. LUTHER, Immanuel F. LUESCHER, 2010. Definition of Key Variables for the Induction of Optimal NY-ESO-1-Specific T Cells in HLA Transgene Mice. In: The Journal of Immunology. 185(6), pp. 3445-3455. ISSN 0022-1767. eISSN 1550-6606

@article{Johannsen2010-09-15Defin-36057, title={Definition of Key Variables for the Induction of Optimal NY-ESO-1-Specific T Cells in HLA Transgene Mice}, year={2010}, doi={10.4049/jimmunol.1001397}, number={6}, volume={185}, issn={0022-1767}, journal={The Journal of Immunology}, pages={3445--3455}, author={Johannsen, Alexandre and Genolet, Raphael and Legler, Daniel F. and Luther, Sanjiv A. and Luescher, Immanuel F.} }

Johannsen, Alexandre Luther, Sanjiv A. Johannsen, Alexandre Legler, Daniel F. eng 2016-11-23T14:49:51Z Luther, Sanjiv A. 2016-11-23T14:49:51Z Luescher, Immanuel F. Definition of Key Variables for the Induction of Optimal NY-ESO-1-Specific T Cells in HLA Transgene Mice Luescher, Immanuel F. An attractive treatment of cancer consists in inducing tumor-eradicating CD8<sup>+</sup> CTL specific for tumor-associated Ags, such as NY-ESO-1 (ESO), a strongly immunogenic cancer germ line gene-encoded tumor-associated Ag, widely expressed on diverse tumors. To establish optimal priming of ESO-specific CTL and to define critical vaccine variables and mechanisms, we used HLA-A2/DR1 H-2<sup>-/-</sup> transgenic mice and sequential immunization with immunodominant DR1- and A2-restricted ESO peptides. Immunization of mice first with the DR1-restricted ESO<sub>123-137</sub> peptide and subsequently with mature dendritic cells (DCs) presenting this and the A2-restriced ESO<sub>157-165</sub> epitope generated abundant, circulating, high-avidity primary and memory CD8<sup>+</sup> T cells that efficiently killed A2/ESO<sub>157-165</sub><sup>+</sup> tumor cells. This prime boost regimen was superior to other vaccine regimes and required strong Th1 cell responses, copresentation of MHC class I and MHC class II peptides by the same DC, and resulted in upregulation of sphingosine 1-phosphate receptor 1, and thus egress of freshly primed CD8<sup>+</sup> T cells from the draining lymph nodes into circulation. This well-defined system allowed detailed mechanistic analysis, which revealed that 1) the Th1 cytokines IFN-gamma and IL-2 played key roles in CTL priming, namely by upregulating on naive CD8<sup>+</sup> T cells the chemokine receptor CCR5; 2) the inflammatory chemokines CCL4 (MIP-1beta) and CCL3 (MIP-1alpha) chemoattracted primed CD4<sup>+</sup> T cells to mature DCs and activated, naive CD8<sup>+</sup> T cells to DC-CD4 conjugates, respectively; and 3) blockade of these chemokines or their common receptor CCR5 ablated priming of CD8(+) T cells and upregulation of sphingosine 1-phosphate receptor 1. These findings provide new opportunities for improving T cell cancer vaccines. Genolet, Raphael Legler, Daniel F. Genolet, Raphael 2010-09-15

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