Arntl deficiency impairs NK cell function by reducing responsiveness to IL-15 and suppressing activation

Natural killer (NK) cells are crucial innate immune effectors with pivotal roles in tumor cytotoxicity and antiviral defense. Arntl (also known as Bmal1), a core circadian rhythm regulator, is essential for maintaining normal immune function; however, its specific regulatory impact on NK cells remains unclear. This study aimed to elucidate the mechanism by which Arntl governs NK cell functionality.

Conditional knockout of Arntl was induced in hematopoietic cells of mice. NK cell abundance, development, and effector functions were assessed in the spleen and bone marrow. Functional assays measured CD107a degranulation, IFN-γsecretion, target cell elimination (MHC-I-deficient cells), activation status, oxidative metabolism, and responsiveness to IL-15.

Through conditional knockout of Arntl in hematopoietic stem cells, we observed a significant reduction in NK cell within the spleen and bone marrow of mice, without impairing NK cell development. Functional assessments revealed that Arntl-deficient NK cells exhibited diminished CD107a degranulation, impaired IFN-γ secretion, and a markedly compromised ability to eliminate MHC-I-deficient target cells. Furthermore, Arntl-deficient NK cells displayed suppressed activation and reduced oxidative metabolism.

Arntl is an important regulator of NK cell immunity. Its deficiency impairs NK cell effector functions by reducing responsiveness to IL-15, providing novel insights into the circadian control of anti-tumor and anti-viral responses.