title: Human invariant natural killer T cells acquire transient innate responsiveness via histone H4 acetylation induced by weak TCR stimulation.
abstract: Invariant NKT cells (iNKT cells) are innate T lymphocytes that are thought to play an important role in producing an early burst of IFN-γ that promotes successful tumor immunosurveillance and antimicrobial immunity. The cellular activation processes underlying innate IFN-γ production remain poorly understood. We show here that weak T cell receptor (TCR) stimulation that does not directly activate iNKT cell IFN-γ messenger RNA transcription nevertheless induces histone H4 acetylation at specific regions near the IFNG gene locus. This renders the iNKT cells able to produce IFN-γ in an innate manner (i.e., not requiring concurrent TCR stimulation) upon exposure to IL-12 and IL-18. The iNKT cells retain the capacity for innate activation for hours to days after the initial weak TCR stimulation, although their innate responsiveness gradually declines as a function of histone deacetylation. These results explain how iNKT cells are able to mediate rapid innate IFN-γ secretion in a manner that does not require them to undergo permanent T(H1) differentiation. Moreover, our results also indicate that iNKT cell motility is maintained during activation by IL-12 and IL-18. Therefore, iNKT cells activated through this pathway can continue to migrate and may thus disseminate the IFN-γ that they produce, which may amplify its impact.
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wang
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Bishop
authors.forename: Subramanya
authors.initials: S
authors.lastname: Hegde
authors.forename: Lance A
authors.initials: LA
authors.lastname: Rodenkirch
authors.forename: J Wesley
authors.initials: JW
authors.lastname: Pike
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gumperz
mesh_terms: D000107:Acetylation; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D018613:Microscopy, Confocal; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050797:STAT4 Transcription Factor / Q000378:metabolism; D059008:Time-Lapse Imaging
chemical_list: D017931:DNA Primers; D006657:Histones; D020382:Interleukin-18; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D018664:Interleukin-12; D007371:Interferon-gamma