Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 209, Issue 5, Pages 987-1000Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20111024
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Funding
- National Institutes of Health [R01 AI060777, R01 AI074940]
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Invariant NKT cells (iNKT cells) are innate T lymphocytes that are thought to play an important role in producing an early burst of IFN-gamma that promotes successful tumor immunosurveillance and antimicrobial immunity. The cellular activation processes underlying innate IFN-gamma production remain poorly understood. We show here that weak T cell receptor (TCR) stimulation that does not directly activate iNKT cell IFN-gamma 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-gamma 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-gamma 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-gamma that they produce, which may amplify its impact.
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