Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity

Area of Science:

• Immunology
• Cellular Biology
• Genetics

Background:

• Fc gamma receptor IIIA (FcγRIIIA), also known as CD16, is crucial for natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC).
• A rare homozygous missense mutation (L66H) in CD16 has been linked to severe herpesvirus infections.
• The precise role of CD16 in NK cell function beyond ADCC remains incompletely understood.

Observation:

• A new patient with the CD16 L66H mutation was identified and their NK cells compared to a previously reported patient.
• Patients with the L66H mutation exhibited intact ADCC but deficient spontaneous NK cell cytotoxicity.
• Decreased surface expression of the coactivation receptor CD2 was observed in patients with the CD16 mutation.

Findings:

• Mechanistic studies in the NK-92 cell line revealed that CD16 expression positively correlated with CD2 surface levels.
• CD16 engagement elicited signaling following CD2 ligation, indicating a functional association.
• The L66H mutation abrogated the association between CD16 and CD2, impairing CD16 signaling after CD2 engagement.

Implications:

• CD16 plays a significant role in NK cell spontaneous cytotoxicity, independent of ADCC, through its interaction with CD2.
• The CD16-CD2 association at the immunological synapse is critical for NK cell effector functions.
• This study uncovers a novel mechanism for human congenital immunodeficiency linked to a specific CD16 mutation and its impact on NK cell function.