Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function

Area of Science:

• Immunology
• Cellular Signaling
• Molecular Biology

Background:

• Natural killer (NK) cell effector functions are critical for immune responses but rely on intricate and not fully understood signaling pathways.
• Activating receptors on NK cells utilize immunotyrosine-based activation motifs (ITAMs) to initiate downstream signaling cascades.
• The adaptor protein SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is a key player in immune cell activation.

Purpose of the Study:

• To investigate the proximal signaling pathways downstream of ITAM-bearing activating receptors in NK cells.
• To elucidate the role of SLP-76 in NK-cell activation and effector functions.
• To identify novel signaling complexes and pathways involved in NK-cell responses.

Main Methods:

• Investigated recruitment of SLP-76 to plasma membrane microclusters in activated NK cells.
• Utilized in vitro and in vivo models to assess the requirement of SLP-76 for NK-cell effector functions.
• Characterized proximal signaling complexes involving SLP-76, including LAT family-dependent and independent pathways.

Main Results:

• SLP-76 recruitment to microclusters is essential for initiating downstream signaling and NK-cell effector functions.
• Two distinct proximal signaling complexes involving SLP-76 were identified: one canonical (LAT-dependent) and one novel (ADAP-dependent).
• Both LAT-dependent and ADAP-dependent pathways contribute to interferon-gamma production and cytotoxicity, but not all SLP-76-dependent events like AKT/ERK phosphorylation or proliferation.

Conclusions:

• NK cells exhibit an unexpected bifurcation in proximal ITAM-mediated signaling pathways.
• Both identified SLP-76-dependent pathways are crucial for optimal NK-cell function, particularly cytotoxicity and cytokine production.
• These findings provide new insights into the complexity of NK-cell activation signaling.