Inflammatory Signals Regulate IL-15 in Response to Lymphodepletion

Area of Science:

• Immunology
• Cell Biology

Background:

• Lymphopenia induction is a therapeutic strategy to boost immune responses against cancer and infections.
• Interleukin-15 (IL-15) is crucial for lymphocyte stimulation post-lymphodepletion, but its regulatory mechanisms remain incompletely understood.

Purpose of the Study:

• To investigate the regulation of IL-15 expression and its forms (cell surface vs. soluble) under various lymphopenic conditions.
• To identify the cellular sources and signaling pathways involved in IL-15 production following different lymphodepletion methods.

Main Methods:

• Induction of lymphopenia using total body irradiation (TBI), cyclophosphamide, and Thy1 antibody-mediated T cell depletion.
• Analysis of cell-specific IL-15 receptor alpha (IL-15Rα) conditional knockout mice.
• Investigation of the stimulator of interferon genes (STING) pathway's role in IL-15 production.

Main Results:

• Cell surface IL-15 expression is upregulated across multiple lymphopenic models, with distinct cellular profiles.
• Soluble IL-15 (sIL-15) complexes are upregulated specifically after TBI or Thy1 antibody treatment.
• Macrophages and dendritic cells are key sources of sIL-15 after TBI, while their contribution differs with Thy1 antibody treatment.
• The STING pathway is a potent inducer of sIL-15 complexes, particularly in response to antibody-mediated T cell depletion and TBI, suggesting cell death products drive production.
• IL-15 induced by inflammatory signals promotes lymphocyte proliferation, demonstrated by IL-15-dependent memory CD8 T cell expansion.

Conclusions:

• The induction, kinetics, cellular sources, and inflammatory signals regulating IL-15 during lymphopenia are highly dependent on the specific method of lymphodepletion used.
• Understanding these differential regulatory mechanisms is critical for optimizing IL-15-based immunotherapies.