title: Combinatorial flexibility of cytokine function during human T helper cell differentiation.
abstract: In an inflammatory microenvironment, multiple cytokines may act on the same target cell, creating the possibility for combinatorial interactions. How these may influence the system-level function of a given cytokine is unknown. Here we show that a single cytokine, interferon (IFN)-alpha, can generate multiple transcriptional signatures, including distinct functional modules of variable flexibility, when acting in four cytokine environments driving distinct T helper cell differentiation programs (Th0, Th1, Th2 and Th17). We provide experimental validation of a chemokine, cytokine and antiviral modules differentially induced by IFN-α in Th1, Th2 and Th17 environments. Functional impact is demonstrated for the antiviral response, with a lesser IFN-α-induced protection to HIV-1 and HIV-2 infection in a Th17 context. Our results reveal that a single cytokine can induce multiple transcriptional and functional programs in different microenvironments. This combinatorial flexibility creates a previously unrecognized diversity of responses, with potential impact on disease physiopathology and cytokine therapy.
authors.affiliation: 1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [3] Laboratoire d'Immunologie Clinique, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Touzot
authors.affiliation: 1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [3] Laboratoire d'Immunologie Clinique, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [4] CIC IGR Curie 1428, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Grandclaudon
authors.affiliation: 1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [3] Laboratoire d'Immunologie Clinique, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [4] INSERM U900, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cappuccio
authors.affiliation: 1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Satoh
authors.affiliation: 1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [3] Laboratoire d'Immunologie Clinique, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Carolina
authors.initials: C
authors.lastname: Martinez-Cingolani
authors.affiliation: 1] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [2] INSERM U900, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Servant
authors.affiliation: 1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Manel
authors.affiliation: 1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [3] Laboratoire d'Immunologie Clinique, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [4] CIC IGR Curie 1428, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Vassili
authors.initials: V
authors.lastname: Soumelis
mesh_terms: D002454:Cell Differentiation / Q000276:immunology*; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018925:Chemokines; D016207:Cytokines; D019707:Receptors, Chemokine; D007371:Interferon-gamma