Requirement for IRF-1 in the microenvironment supporting development of natural killer cells

Natural killer (NK) cells are critical for both innate and adaptive immunity(1,2). The development of NK cells requires interactions between their progenitors and the bone-marrow microenvironment(3-6); however, little is known about the molecular nature of such interactions, Mice that do not express the transcription factor interferon-regulatory factor-1 (IRF-1; such mice are IRF-1(-/-) mice) have been shown to exhibit a severe NK-cell deficiency(7,8). Here we demonstrate that the lack of IRF-1 affects the radiation-resistant cells that constitute the microenvironment required for NK-cell development, but not the NK-cell progenitors themselves. We also show that IRF-1(-/-) bone-marrow cells can generate functional NK cells when cultured with the cytokine interleukin-15 (refs 9-12) and that the interleukin-15 gene is transcriptionally regulated by IRF-1. These results reveal, for the first time, a molecular mechanism by which the bone-marrow microenvironment supports NK-cell development.