IFN Regulatory Factor-2 Deficiency Revealed a Novel Checkpoint Critical for the Generation of Peripheral NK Cells

Abstract

NK cell development is far less understood compared with that of T and B cells despite the critical importance of NK cells in innate immunity. Mice lacking the transcription factor IFN regulatory factor-2 (IRF-2) are known to exhibit NK cell deficiency. However, the role of IRF-2 in NK cell development has remained unclear. In this study we found that NK cell deficiency in the periphery in IRF-2-deficient mice was due to selective loss of mature NK cells, but not to maturation arrest, and NK cells in these mice exhibited very immature surface phenotypes (CD11blowDx5low) with highly compromised NK receptor expression. In contrast, IRF-2-deficient NK cells in bone marrow (BM) showed relatively mature phenotypes (CD11blowDx5high) with less compromised NK receptor repertoire. Furthermore, BM NK cells in IRF-2-deficient mice were found to proliferate almost normally, but underwent accelerated apoptosis. These observations indicated that NK cell maturation could advance up to a late, but not the final, stage in the BM, whereas these cells were incapable of contributing to the peripheral NK cell pool due to premature death in the absence of IRF-2. In contrast, NK cell numbers and Ly49 expression were much more severely reduced in BM in IL-15-deficient mice than in IRF-2−/− mice. The differential peripheral and central NK cell deficiencies in IRF-2−/− mice thus revealed a novel late checkpoint for NK cell maturation, distinct from the early IL-15-dependent expansion stage.

IFN Regulatory Factor-2 Regulates Macrophage Apoptosis through a STAT1/3- and Caspase-1-Dependent Mechanism

“…In this study, we show that the lack of IRF-2 renders macrophages significantly more sensitive to apoptotic stimuli, supporting our previous observations that Kupffer cells from IRF-2 Ϫ/Ϫ mice are more sensitive to apoptosis basally and after LPS (34). Supporting the antiapoptotic function of IRF-2 presented in this work, Taki et al (35) recently reported that bone marrow-derived NK cells from IRF-2 Ϫ/Ϫ mice proliferated almost normally, but underwent accelerated apoptosis.…”

“…Although IRF-2 has previously been related to apoptosis regulation (34,35,58), the mechanism still remains unclear. In this study, we show that the lack of IRF-2 renders macrophages significantly more sensitive to apoptotic stimuli, supporting our previous observations that Kupffer cells from IRF-2 Ϫ/Ϫ mice are more sensitive to apoptosis basally and after LPS (34).…”

“…We suggested a role for IRF-2 in apoptosis after detecting greater numbers of apoptotic Kupffer cells in the livers of IRF-2 Ϫ/Ϫ mice when compared with wild-type littermates (34). Recently, the absence of IRF-2 has been shown to cause premature apoptosis of NK cells (35); however, the mechanism(s) by which IRF-2 regulates apoptosis is unknown.…”

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

“…This hypothesis is supported by the findings that only CD11b low CD43 À NK cells are present in mice deficient for several different transcription factors, such as GATA-3, IRF2 or T-bet, and in mice bearing constitutively active NFkB. In all these models, the CD11b low CD43 À NK cells exhibit normal cytotoxic capacities [38][39][40][41].…”

“…This hypothesis is supported by the findings that only CD11b low CD43 À NK cells are present in mice deficient for several different transcription factors, such as GATA-3, IRF2 or T-bet, and in mice bearing constitutively active NFkB. In all these models, the CD11b low CD43 À NK cells exhibit normal cytotoxic capacities [38][39][40][41].In our study, we found that splenic NK cells from CD70-Tg mice, whether stimulated through the IL-12/IL-18 receptor or through the NK1.1 receptor, produced less IFN-g compared with WT NK cells, whereas in liver no differences were demonstrated. Regarding cytotoxicity, both liver and splenic NK cells from CD70-Tg mice showed increased activity.…”