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An XBP1s-PIM-2 positive feedback loop controls IL-15-mediated survival of natural killer cells

Shoubao Ma1,2, Jingjing Han1,2, Zhenlong Li1,2

  • 1Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA 91010, USA.

Science Immunology
|March 10, 2023
PubMed

Insights

Interleukin-15 (IL-15) signaling uses spliced X-box-binding protein 1 (XBP1s) to control natural killer (NK) cell survival and function. XBP1s targets PIM-2 for survival and T-bet for effector functions, revealing a novel regulatory mechanism.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Spliced X-box-binding protein 1 (XBP1s) is a transcription factor crucial for natural killer (NK) cell survival and function, downstream of IL-15 and AKT signaling.
  • The precise downstream targets and regulatory mechanisms of XBP1s in NK cells remain largely unelucidated.

Purpose of the Study:

  • To investigate the role of XBP1s in IL-15-mediated NK cell survival, proliferation, and effector functions.
  • To identify the downstream targets of XBP1s that mediate these functions in NK cells.

Main Methods:

  • Utilized XBP1 conditional knockout mice to study NK cell function in vivo and in vitro.
  • Employed molecular biology techniques to identify XBP1s targets and regulatory interactions.

Main Results:

  • XBP1s is essential for IL-15-driven NK cell survival, but not proliferation, both in vitro and in vivo.
  • XBP1s targets the anti-apoptotic gene PIM-2, which stabilizes XBP1s protein via phosphorylation.
  • XBP1s enhances NK cell effector functions and antitumor immunity by recruiting T-bet to the Interferon-gamma (Ifng) promoter.

Conclusions:

  • IL-15-XBP1s signaling is a critical pathway regulating NK cell survival and effector functions.
  • PIM-2 and T-bet are key downstream targets of XBP1s, mediating its effects on NK cell homeostasis and antitumor immunity.

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