Transcription Factor IRF8 Orchestrates the Adaptive Natural Killer Cell Response

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.

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

“…This hypothesis was strengthened by the study of Irf8 −/− mice, who were found to have decreased frequency of terminally mature NK cells in peripheral blood and spleen . Further study of these mice showed that they are particularly susceptible to LCMV infection and malignancy and that generation of adaptive NK cells in these mice following infection is impaired . In both murine and human NK cells, IRF8 is up‐regulated in response to cytokine signaling, and in mice, this leads to Stat4‐mediated binding of Irf8 to the cell cycle regulator Zbtb32.…”

“…Further study of these mice showed that they are particularly susceptible to LCMV infection and malignancy and that generation of adaptive NK cells in these mice following infection is impaired . In both murine and human NK cells, IRF8 is up‐regulated in response to cytokine signaling, and in mice, this leads to Stat4‐mediated binding of Irf8 to the cell cycle regulator Zbtb32. In this way, viral infection or expansion in response to tumor challenge leads to Irf8‐mediated NK cell expansion and generation of the NK cell memory pool …”

“…In both murine and human NK cells, IRF8 is up‐regulated in response to cytokine signaling, and in mice, this leads to Stat4‐mediated binding of Irf8 to the cell cycle regulator Zbtb32. In this way, viral infection or expansion in response to tumor challenge leads to Irf8‐mediated NK cell expansion and generation of the NK cell memory pool …”

“…Together, these data suggest that, in both mice and humans, there is a critical link between NK cell development, proliferation, and functional maturation. Given the requirement for IRF8‐driven NK cell expansion, mediated by the cell cycle regulator Zbtb32, in the generation of adaptive NK cells in mice, it is plausible to think that this expansion is the feature that is “broken” in NK cells from patients with CMG complex or biallelic IRF8 mutations. It remains to be seen how this so dramatically affects the function of remaining NK cells in these patients, however, particularly given the presumed retained function of the NK cells in patients with hypomorphic RAG mutations …”

Transcriptional control of natural killer cell differentiation

“…Functionally, STAT4 acts in part by directing a ‘permissive’ chromatin state, likely through the recruitment of histone remodeling enzymes, around target gene loci. Indeed, H3K4 trimethylation at the Runx , Cbfb , and Irf8 promoters was recently shown to occur in a STAT4‐dependent manner during NK cell activation in vitro . The related TF, STAT1 also contributes to the expansion of MCMV‐specific Ly49H + NK cells, acting downstream of type 1 interferon (IFN‐I) signals that serve to protect NK cells from NKG2D‐dependent fratricide .…”