The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development

Gascoyne DM, et al. Nat Immunol. 2009 Oct;10(10):1118-24

Speaker: Hsu-En Chang (張許恩)                      Time:  15:10~16:10, Nov.18, 2009

Commentator: Pei-Jung Lu (呂佩融老師)            Place:  Room 601

Abstract:

        Natural killer (NK) cells are a subset of lymphocytes crucial for innate immunity and modification of adaptive immune responses. It develops mainly in the bone marrow. Hematopoietic stem cells give rise to CD122⁺NK1.1–NK cell precursors (NKPs) in the present oftranscription factors Ets-1, Ikaros, PU.1, and Id2. NKPs give rise to immature NK (iNK) cells in the present of transcription factors Gata-3, Irf-2, and T-bet, and then become mature NK (mNK) in the present of transcription factors (TFs) CEBP-γ, �z�nMEF, and MITF. Despite so many TFs that are found to be participate in NK cell development, none of them is reported to be specific in the NK lineage. In this paper, the authors claimed that they might discover the first TF that is specific in NK lineage, E4bp4, which also called NfiL3.They first demonstrated the expression of E4bp4 in NK and NKT cells by measuring the expression of E4bp4 in mouse B, T, NKT and NK cell populations. They also found the specific loss of NK cells in E4bp4–/– mice, and proved the requirement for E4bp4 in NK cell production was cell intrinsic in an in vivo adoptive transfer experiments with bone marrow. They transferred bone marrow from wild-type (Ly5.1+) mice into sublethally irradiated E4bp4–/– (Ly5.2+) mice, and repopulated the NK lineage both in the short term and long term. They showed that E4bp4 increased NK cell production by directly promoting NK lineage commitment by culturing HPCs on stromal cells OP9 in the presence of cytokines required for NK cell maturation. The authors also demonstrated an upstream-downstream relationship of IL-15, E4bp4, and Id2 by a series of culture experiments that compared cell populations and TF mRNA expressions between wild type, knock out, and retroviral transduced cells.

References:

1.       Di Santo, J.P. Natural killer cell developmental pathways: a question of balance. Annu. Rev. Immunol. 24, 257–286 (2006).

2.       Vivier, E., Tomasello, E., Baratin, M., Walzer, T. & Ugolini, S. Functions of natural killer cells. Nat. Immunol. 9, 503–510 (2008).