Title | Transcription Factor IRF8 Orchestrates the Adaptive Natural Killer Cell Response. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Adams NM, Lau CM, Fan X, Rapp M, Geary CD, Weizman O-E, Diaz-Salazar C, Sun JC |
Journal | Immunity |
Volume | 48 |
Issue | 6 |
Pagination | 1172-1182.e6 |
Date Published | 2018 06 19 |
ISSN | 1097-4180 |
Keywords | Adaptive Immunity, Animals, Herpesviridae Infections, Interferon Regulatory Factors, Killer Cells, Natural, Lymphocyte Activation, Mice, Muromegalovirus |
Abstract | Natural killer (NK) cells are innate lymphocytes that display features of adaptive immunity during viral infection. Biallelic mutations in IRF8 have been reported to cause familial NK cell deficiency and susceptibility to severe viral infection in humans; however, the precise role of this transcription factor in regulating NK cell function remains unknown. Here, we show that cell-intrinsic IRF8 was required for NK-cell-mediated protection against mouse cytomegalovirus infection. During viral exposure, NK cells upregulated IRF8 through interleukin-12 (IL-12) signaling and the transcription factor STAT4, which promoted epigenetic remodeling of the Irf8 locus. Moreover, IRF8 facilitated the proliferative burst of virus-specific NK cells by promoting expression of cell-cycle genes and directly controlling Zbtb32, a master regulator of virus-driven NK cell proliferation. These findings identify the function and cell-type-specific regulation of IRF8 in NK-cell-mediated antiviral immunity and provide a mechanistic understanding of viral susceptibility in patients with IRF8 mutations. |
DOI | 10.1016/j.immuni.2018.04.018 |
Alternate Journal | Immunity |
PubMed ID | 29858012 |
PubMed Central ID | PMC6233715 |
Grant List | R01 AI100874 / AI / NIAID NIH HHS / United States T32 CA009149 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States F30 AI122721 / AI / NIAID NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States F30 AI136239 / AI / NIAID NIH HHS / United States R01 AI130043 / AI / NIAID NIH HHS / United States |
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