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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2010
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The Journal of Immunology ; 185 (2010), 6. - pp. 3445-3455. - ISSN 0022-1767. - eISSN 1550-6606
Abstract
An attractive treatment of cancer consists in inducing tumor-eradicating CD8+ 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-/- transgenic mice and sequential immunization with immunodominant DR1- and A2-restricted ESO peptides. Immunization of mice first with the DR1-restricted ESO123-137 peptide and subsequently with mature dendritic cells (DCs) presenting this and the A2-restriced ESO157-165 epitope generated abundant, circulating, high-avidity primary and memory CD8+ T cells that efficiently killed A2/ESO157-165+ 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+ 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+ T cells the chemokine receptor CCR5; 2) the inflammatory chemokines CCL4 (MIP-1beta) and CCL3 (MIP-1alpha) chemoattracted primed CD4+ T cells to mature DCs and activated, naive CD8+ 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.
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JOHANNSEN, Alexandre, Raphael GENOLET, Daniel 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. Available under: doi: 10.4049/jimmunol.1001397BibTex
@article{Johannsen2010-09-15Defin-36057, year={2010}, doi={10.4049/jimmunol.1001397}, title={Definition of Key Variables for the Induction of Optimal NY-ESO-1-Specific T Cells in HLA Transgene Mice}, number={6}, volume={185}, issn={0022-1767}, journal={The Journal of Immunology}, pages={3445--3455}, author={Johannsen, Alexandre and Genolet, Raphael and Legler, Daniel and Luther, Sanjiv A. and Luescher, Immanuel F.} }
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