title: Impact of Exogenous Galectin-9 on Human T Cells: CONTRIBUTION OF THE T CELL RECEPTOR COMPLEX TO ANTIGEN-INDEPENDENT ACTIVATION BUT NOT TO APOPTOSIS INDUCTION.
abstract: Galectin-9 (gal-9) is a multifunctional β-galactoside-binding lectin, frequently released in the extracellular medium, where it acts as a pleiotropic immune modulator. Despite its overall immunosuppressive effects, a recent study has reported bimodal action of gal-9 on human resting blood T cells with apoptosis occurring in the majority of them, followed by a wave of activation and expansion of Th1 cells in the surviving population. Our knowledge of the signaling events triggered by exogenous gal-9 in T cells remains limited. One of these events is cytosolic calcium (Ca(2+)) release reported in some murine and human T cells. The aim of this study was to investigate the contribution of Ca(2+) mobilization to apoptotic and nonapoptotic effects of exogenous gal-9 in human T cells. We found that the T cell receptor (TCR)-CD3 complex and the Lck kinase were required for Ca(2+) mobilization but not for apoptosis induction in Jurkat cells. These data were confirmed in human CD4(+) T cells from peripheral blood as follows: a specific Lck chemical inhibitor abrogated Ca(2+) mobilization but not apoptosis induction. Moreover, Lck activity was also required for the production of Th1-type cytokines, i.e. interleukin-2 and interferon-γ, which resulted from gal-9 stimulation in peripheral CD4(+) T cells. These findings indicate that gal-9 acts on T cells by two distinct pathways as follows: one mimicking antigen-specific activation of the TCR with a mandatory contribution of proximal elements of the TCR complex, especially Lck, and another resulting in apoptosis that is independent of this complex.
authors.affiliation: From the Université Paris-Sud, 15 Rue Georges Clémenceau, 91400, Orsay, France, the CNRS, UMR 8126, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France, the Cellvax, Ecole Nationale Vétérinaire d'Alfort, 7 Avenue du Général de Gaulle, 94704 Maisons-Alfort Cedex, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Lhuillier
authors.affiliation: From the Université Paris-Sud, 15 Rue Georges Clémenceau, 91400, Orsay, France, the CNRS, UMR 8126, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France, the Cellvax, Ecole Nationale Vétérinaire d'Alfort, 7 Avenue du Général de Gaulle, 94704 Maisons-Alfort Cedex, France.
authors.forename: Clément
authors.initials: C
authors.lastname: Barjon
authors.affiliation: the Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan, the GalPharma Co., Ltd., Takamatsu, Kagawa 761-0301, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.affiliation: the CNRS, UMR 8126, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Gelin
authors.affiliation: INSERM, UMR-S 938, Centre de Recherche Saint-Antoine, 75012, Paris, France, the Sorbonne Universités, UPMC Université Paris 06, UMR-S 938, Centre de Recherche Saint-Antoine, 75012, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Praz
authors.affiliation: CNRS, UMR 8161 Groupe IRCV, Institut de Biologie de Lille, 1 Rue du Pr. Calmette, 59021 Lille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Morales
authors.affiliation: From the Université Paris-Sud, 15 Rue Georges Clémenceau, 91400, Orsay, France, UMR 8122, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France, and.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Souquere
authors.affiliation: the Department of Immunology and Immunopathology, Faculty of Medicine, Kagawa University, Kagawa 761-0793, Japan, the GalPharma Co., Ltd., Takamatsu, Kagawa 761-0301, Japan.
authors.forename: Mitsuomi
authors.initials: M
authors.lastname: Hirashima
authors.affiliation: the Cellvax, Ecole Nationale Vétérinaire d'Alfort, 7 Avenue du Général de Gaulle, 94704 Maisons-Alfort Cedex, France.
authors.forename: Ming
authors.initials: M
authors.lastname: Wei
authors.affiliation: From the Université Paris-Sud, 15 Rue Georges Clémenceau, 91400, Orsay, France, INSERM, UMR-S 757, Bâtiment 440/443, Rue des Adèles, 91405 Orsay, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dellis
authors.affiliation: From the Université Paris-Sud, 15 Rue Georges Clémenceau, 91400, Orsay, France, the CNRS, UMR 8126, Institut Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif Cedex, France, pierre.busson@gustaveroussy.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Busson
mesh_terms: D017209:Apoptosis; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D037161:Galectins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D037161:Galectins; C105032:LGALS9 protein, human; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium
keywords: Lck; T-cell receptor (TCR); apoptosis; calcium; galectin-9; interferon; interleukin