IL-15 Priming Alters IFN-γ Regulation in Murine NK Cells.

Area of Science:

• Immunology
• Cellular and Molecular Immunology
• Cytokine Signaling

Background:

• Natural killer (NK) cells are crucial for innate immunity, mediating effector functions through cytokine signaling and receptor engagement.
• NK cell production of interferon-gamma (IFN-γ) is tightly regulated, with distinct mechanisms governing transcription and protein production.
• Resting NK cells show activation-specific metabolic needs for IFN-γ production, which shift after IL-15 priming.

Purpose of the Study:

• To investigate how ex vivo IL-15 priming alters NK cell regulatory networks.
• To determine if IL-15 priming enables IFN-γ transcription upon activating receptor engagement in NK cells.
• To elucidate the transcriptional signature associated with IFN-γ production in primed NK cells.

Main Methods:

• Murine NK cells were cultured with or without IL-15 priming and stimulated via activating receptors or cytokines.
• Transcriptional analysis (RNA sequencing) was performed on naive, low-dose IL-15 treated, and primed NK cells.
• Chromatin accessibility, ITAM signaling, and c-Myc (Myc) expression were assessed in relation to Ifng transcription.

Main Results:

• IL-15 priming induced Ifng transcript upregulation following activating receptor stimulation, unlike in naive NK cells.
• This transcriptional regulation was independent of chromatin accessibility changes or altered ITAM signaling.
• A distinct transcriptional signature, including c-Myc targets, was associated with Ifng transcription in primed NK cells, though Myc itself was not essential.

Conclusions:

• Ex vivo IL-15 priming reprograms NK cells, enabling Ifng transcription upon activating receptor stimulation.
• Altered regulatory networks and distinct gene expression patterns underlie this shift in IFN-γ regulation.
• This finding provides new insights into the control of NK cell-mediated immune responses.