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Nat Commun. 2014 May 28;5:3987. doi: 10.1038/ncomms4987.

Combinatorial flexibility of cytokine function during human T helper cell differentiation.

Author information

1
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.
2
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.
3
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.
4
1] INSERM U932, 26 rue d'Ulm, 75005 Paris, France [2] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
5
1] Section Recherche, Institut Curie, 26 rue d'Ulm, 75005 Paris, France [2] INSERM U900, 26 rue d'Ulm, 75005 Paris, France.

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.

PMID:
24865484
DOI:
10.1038/ncomms4987
[Indexed for MEDLINE]

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