T _H 17 Cell Differentiation Is Regulated by the Circadian Clock

Abstract

Circadian clocks regulate numerous physiological processes that vary across the day-night (diurnal) cycle, but if and how the circadian clock regulates the adaptive immune system is mostly unclear. Interleukin-17-producing CD4+ T helper (Th17) cells are proinflammatory immune cells that protect against bacterial and fungal infections at mucosal surfaces. Their lineage specification is regulated by the orphan nuclear receptor RORγt. We show that the transcription factor NFIL3 suppresses Th17 cell development by directly binding and repressing the Rorγt promoter. NFIL3 links Th17 cell development to the circadian clock network through the transcription factor REV-ERBα. Accordingly Th17 lineage specification varies diurnally and is altered in Rev-erbα−/− mice. Light cycle disruption elevated intestinal Th17 cell frequencies and increased susceptibility to inflammatory disease. Thus, lineage specification of a key immune cell is under direct circadian control.

IL-10: Master Switch from Tumor-Promoting Inflammation to Antitumor Immunity

“…In the absence of RORgt, cytotoxic granzymes and perforin-positive cells are increased in the gut, indicating the activity of cytotoxic immunosurveillance. Interestingly, the expression of RORgt is also repressed by NFIL3 (27), a transcriptional repressor mediating the IL-10-induced inhibition of IL-12/23p40 expression (14). These data demonstrate the intricate antagonism of proinflammatory and proimmunity signaling and the importance of IL-10 in the control of Th17 cells that drive tumor-promoting inflammation.…”

Immunometabolism: Is it under the eye of the clock?

“…Double knockout of ROR␣ and ROR␥ leads to complete ablation of Th17 cells, making these mice resistant to EAE [133,134]. The transcription factor Nuclear Factor Interleukin 3 regulated (NFIL3) was found to suppress Th17 cell development by binding to and repressing the Ror t promoter [135]. Further linking the clock to this process is that Nfil3 is directly suppressed by REV-ERB␣.…”

“…Further linking the clock to this process is that Nfil3 is directly suppressed by REV-ERB␣. Rev-erb˛ -/-mice displayed greater NFIL3, lower ROR␥t and subsequently a decreased capacity for Th17 cell development [135].…”

Cutting Edge: Salivary Gland NK Cells Develop Independently of Nfil3 in Steady-State

“…The differentiation of iNK cells from NK cell precursors requires transpresentation of IL-15 by membrane-bound Il15ra, as well as a basic leucine zipper transcriptional activator, known as Nfil3 or E4bp4 (3)(4)(5)(6). Nfil3 also plays a role in development and/or function of macrophages, CD8a dendritic cells, CD4 T cells, and B cells (6,7). NK cell development requires at least two additional transcription factors: T-bet promotes the stability of iNK cells, whereas Eomesodermin (Eomes) is required for the generation of mature NK cells (8).…”