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Human Lymphocyte Activation Gene-3 Molecules Expressed by Activated T Cells Deliver Costimulation Signal for Dendritic Cell Activation¹

Chiara Casati^*, Chiara Camisaschi^*, Luisa Novellino^*, Arabella Mazzocchi, Frédéric Triebel, Licia Rivoltini^*, Giorgio Parmiani^2,* and Chiara Castelli^3,*

^* Unit of Immunotherapy of Human Tumor and Unit of Immunohematology, Fondazione Instituto di Ricerca e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milano, Italy; and Faculté de Pharmacie, Immutep, Chatenay-Malabry, France

Data have been reported on the in vivo adjuvant role of soluble lymphocyte activation gene-3 (LAG-3) recombinant protein in mouse models and on its ability to support the in vitro generation of human, tumor-specific CTLs. In this study, we show that soluble human rLAG-3 protein (hLAG-3Ig) used in vitro as a single maturation agent induces phenotypic maturation of monocyte-derived dendritic cells and promoted the production of chemokines and TNF- inflammatory cytokine. When given in association with optimal or suboptimal doses of CD40/CD40L, hLAG-3Ig functions as a strong costimulatory factor and induces full functional activation of monocyte-derived dendritic cells that includes the production of high level of IL-12p70. Moreover, evidence is here provided that this costimulatory function licensing dendritic cells to produce IL-12p70 is also a functional property of LAG-3 molecules when expressed in a physiological context by CD4⁺ activated T cells. Altogether, these data show for the first time a role of LAG-3 in mediating dendritic cell activation when expressed on the T cell surface or released after specific Ag stimulation in the interspaces of immunological synapses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro (Milano) and the European Community (Cancer Immunotherapy, Contract 518234). C. Casati is a fellow of Fondazione Italiana per Ricerca sul Cancro (Milano).

² Current address: Unit of Immunobiotherapy of Solid Tumors, San Raffaele Scientific Institute, Milano, Italy.

³ Address correspondence and reprint requests to Dr. Chiara Castelli, Unit of Immunotherapy of Human Tumors, Fondazione Instituto di Ricerca e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Via G Venezian 1, 20133 Milano, Italy. E-mail address: chiara.castelli{at}istitutotumori.mi.it

⁴ Abbreviations used in this paper: DC, dendritic cell; LAG-3, lymphocyte activation gene-3; MoDC, monocyte-derived DC; hLAG-3Ig, human recombinant LAG-3 protein; iMoDC, immature monocyte-derived DC; CBA, cytometric bead array.