Adaptive Natural Killer Cells Integrate Interleukin-18 during Target-Cell Encounter

Area of Science:

• Immunology
• Virology
• Cellular Biology

Background:

• Human cytomegalovirus (HCMV) infection causes adaptive changes in natural killer (NK) cells.
• Adaptive NK cells, particularly NKG2C+ subsets, show strong effector functions but are poorly responsive to IL-12 and IL-18 stimulation.

Purpose of the Study:

• To investigate if adaptive NK cells can functionally integrate pro-inflammatory cytokines (IL-12 and IL-18) in specific contexts.
• To determine the role of cytokine costimulation in adaptive NK cell responses during target cell activation.

Main Methods:

• Co-culturing adaptive NKG2C+ NK cells with target cells in the presence of pro-inflammatory cytokines.
• Measuring cytokine production (IFN-gamma, TNF) and assessing effects on bystander endothelial cells.
• Functional assays to evaluate the role of IL-18 in costimulation.

Main Results:

• Adaptive NKG2C+ NK cells can be costimulated by pro-inflammatory cytokines during target cell activation.
• Cytokine costimulation enhances interferon-gamma and tumor necrosis factor production.
• This costimulation promotes HLA class I and adhesion molecule expression, and antiviral gene transcription in bystander endothelial cells.
• Interleukin-18 (IL-18) was identified as the key driver of costimulation, sufficient for elevated cytokine production even without IL-12.

Conclusions:

• Adaptive NKG2C+ NK cells integrate IL-18 as a costimulatory signal during target cell encounters, rather than being completely unresponsive.
• This integration enhances NK cell effector functions and impacts surrounding cells, contributing to the immune response against HCMV.
• IL-18 plays a critical role in modulating adaptive NK cell responses in a context-dependent manner.