title: Deficiency of N-myristoylation reveals calcineurin activity as regulator of IFN-γ-producing γδ T cells.
abstract: γδ T cell subsets can be characterized, in part, by their secretion of select proinflammatory cytokines. The molecular mechanisms driving the diverse fates of γδ T cells have not been elucidated. We have previously shown that the attachment of myristic acid to the N-terminal glycine of proteins, termed N-myristoylation, is essential for αβ T cell development and activation. Here, we explore the potential role of this lipid modification on the activation of γδ T cells. In the absence of N-myristoylation, the CD27+γδ T cell subset was dominantly affected. The cells produced high levels of IFN-γ upon stimulation. In addition, they were more sensitive to inhibition of the CaN-Nfat pathway than were γδ T cells with myristoylated CaN. N-Myristoylation was found to modulate activity of phosphatase CaN, a regulator of Nfat. In summary, the CaN-Nfat pathway regulates development and function of IFN-γ-producing γδ T cells, and its balanced activity is strongly dependent on CaN N-myristoylation.
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rampoldi
authors.affiliation: Division of Developmental Immunology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Brunk
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Bonrouhi
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Federico
authors.affiliation: Light Microscopy Facility, German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Damir
authors.initials: D
authors.lastname: Krunic
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.|Institute of Pathology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Porubsky
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; h.-j.groene@dkfz.de.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; z.popovic@dkfz.de.|Institute of Pathology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Zoran V
authors.initials: ZV
authors.lastname: Popovic
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019814:Myristic Acid / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000098815:T-bet Transcription Factor
chemical_list: D050778:NFATC Transcription Factors; D016692:Receptors, Antigen, T-Cell, gamma-delta; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019814:Myristic Acid; D007371:Interferon-gamma; D019703:Calcineurin
keywords: CD27+ γδ T cells; Calcineurin-Nfatc pathway; IFN-γ; IL-17A