title: IL-15.IL-15Rα complex shedding following trans-presentation is essential for the survival of IL-15 responding NK and T cells.
abstract: Interleukin (IL)-15 and its specific receptor chain, IL-15Rα, support the development of various effector cells, including NK and CD8 T cells via a mechanism called trans-presentation. Whereas the dynamic of trans-presentation has been shown to involve the recycling of IL-15Rα by presenting cells, the way responding cells integrate, or take advantage of this process has not been evaluated yet. To address this question, we set up a trans-presentation model using a membrane-bound IL-15.IL-15Rα fusion protein, and found that IL-15 is detectable within responding cells following IL-15 trans-presentation. The role of the proteolytic cleavage of IL-15Rα in this process was investigated by generating an uncleavable form of IL-15Rα. We showed that IL-15 entry into responding cells necessitates the cleavage of IL-15.IL-15Rα complex from the surface of IL-15 presenting cells, and observed that IL-15Rα cleavage is associated with a decrease of the duration of Stat5 signaling. Once separated from presenting cells, responding cells are able to recycle IL-15.IL-15Rα complexes via intracellular compartments, for residual proliferation in a time-limited manner. These studies define an unprecedented cytokine pathway in which the IL-15.IL-15Rα complex cleaved from presenting cells allows responding cells to internalize, store and use IL-15.IL-15Rα complex for their own proliferation and survival.
authors.affiliation: Cancer Research Center Nantes-Angers, Inserm Unité Mixte de Recherche 892, Centre National de la Recherche Scientifique 6299, University of Nantes, 44007 Nantes, France;
authors.forename: Fella
authors.initials: F
authors.lastname: Tamzalit
authors.affiliation: Cancer Research Center Nantes-Angers, Inserm Unité Mixte de Recherche 892, Centre National de la Recherche Scientifique 6299, University of Nantes, 44007 Nantes, France;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Barbieux
authors.affiliation: Cancer Research Center Nantes-Angers, Inserm Unité Mixte de Recherche 892, Centre National de la Recherche Scientifique 6299, University of Nantes, 44007 Nantes, France;
authors.forename: Ariane
authors.initials: A
authors.lastname: Plet
authors.affiliation: Cancer Research Center Nantes-Angers, Inserm Unité Mixte de Recherche 892, Centre National de la Recherche Scientifique 6299, University of Nantes, 44007 Nantes, France;
authors.forename: Julie
authors.initials: J
authors.lastname: Heim
authors.affiliation: PiCell Facility, SFR Bonamy, FED 4203, Unité Mixte de Service 016, 44007 Nantes, France; and.
authors.forename: Steven
authors.initials: S
authors.lastname: Nedellec
authors.affiliation: Cancer Research Center Nantes-Angers, Inserm Unité Mixte de Recherche 892, Centre National de la Recherche Scientifique 6299, University of Nantes, 44007 Nantes, France;Centre Hospitalier Universitaire, Nantes Hospital, 44093 Nantes, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Morisseau
authors.affiliation: Cancer Research Center Nantes-Angers, Inserm Unité Mixte de Recherche 892, Centre National de la Recherche Scientifique 6299, University of Nantes, 44007 Nantes, France;
authors.forename: Yannick
authors.initials: Y
authors.lastname: Jacques
authors.affiliation: Cancer Research Center Nantes-Angers, Inserm Unité Mixte de Recherche 892, Centre National de la Recherche Scientifique 6299, University of Nantes, 44007 Nantes, France; erwan.mortier@inserm.fr.
authors.forename: Erwan
authors.initials: E
authors.lastname: Mortier
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008856:Microscopy, Fluorescence; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D050799:STAT5 Transcription Factor
keywords: IL-2Rβ; autocrine; cell–cell interaction; lymphocyte; synapse