Regulation of Adaptive and Innate Immunity by the Circadian Transcription Factor NFIL3
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The day-night cycle has a profound impact on animal physiology, which has been shown to be mediated by an intracellular timing system called the circadian clock. However, little is known about whether and how the day-night cycle and the circadian clock influence host immunity. Here, I show that the circadian transcription factor NFIL3 is critical for both adaptive and innate immunity by regulating TH17 cells and innate lymphoid cells (ILCs), respectively. First, NFIL3 transcriptionally represses RORgt, the master regulator of TH17 cells, by directly binding to the Rorgt promoter and thereby suppresses TH17 cell development from naïve T helper cells. Consistent with oscillation of Nfil3 expression during the circadian cycle, Rorgt expression also oscillates in mice, with higher expression at noon and lower expression at midnight. Accordingly, naïve T helper cells show greater potential to develop into TH17 cells at noon than at midnight. Furthermore, artificially disturbing the circadian cycles of mice by manipulating their light exposure results in circadian clock-mediated disruption of TH17 homeostasis and increased susceptibility to experimentally-induced colitis. Therefore, NFIL3 regulates TH17 cell development in a circadian manner. Second, NFIL3 is essential for the development of all major types of innate lymphoid cells (ILCs) by regulating the generation of ILC progenitors in the bone marrow. One of the NFIL3-dependent progenitor populations, aLP, can differentiate into all major types of ILCs in vivo. NFIL3 controls progenitor development by activating a High Mobility Group (HMG) transcription factor Tox directly in common lymphoid progenitors (CLPs). Accordingly, restoring Tox expression in Nfil3-deficient progenitors rescues ILC development in mice. So NFIL3 regulates ILC development by activating Tox expression in bone marrow precursors. Taken together, my work demonstrates that NFIL3 is a critical regulator of host immunity and that it modulates immune functions along the circadian cycle. This study is among the first to reveal the influence of the circadian clock on host immunity and provides novel insights into the regulatory mechanisms underlying variations of immune cell development and function during the circadian cycle.