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IFN Regulatory Factor-2 Deficiency Revealed a Novel Checkpoint Critical for the Generation of Peripheral NK Cells ¹

Shinsuke Taki^2,*, Shinsuke Nakajima^*, Eri Ichikawa^*, Takashi Saito and Shigeaki Hida^*

^* Department of Immunology and Infectious Diseases, Shinshu University Graduate School of Medicine, Matsumoto, Japan; and Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

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 (CD11b^lowDx5^low) with highly compromised NK receptor expression. In contrast, IRF-2-deficient NK cells in bone marrow (BM) showed relatively mature phenotypes (CD11b^lowDx5^high) 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.

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