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Published on: March 14, 2011
Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity
Jennifer T Grier1, Lisa R Forbes, Linda Monaco-Shawver
1Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA.
Insights
A specific mutation in the Fc receptor CD16 impairs natural killer (NK) cell spontaneous cytotoxicity by disrupting its association with the CD2 coactivation receptor. This discovery sheds light on a novel mechanism of human congenital immunodeficiency.
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.
Abstract:
The Fc receptor on NK cells, FcγRIIIA (CD16), has been extensively studied for its role in mediating antibody-dependent cellular cytotoxicity (ADCC). A homozygous missense mutation in CD16 (encoding a L66H substitution) is associated with severe herpesvirus infections in rare patients. Here, we identified a new patient with this CD16 mutation and compared the patient's NK cells to those of the originally reported patient. Patients with the L66H mutation had intact ADCC, but deficient spontaneous NK cell cytotoxicity and decreased surface expression of CD2, a coactivation receptor. Mechanistic studies in a human NK cell line, NK-92, demonstrated that CD16 expression correlated with CD2 surface levels and enabled killing of a melanoma cell line typically resistant to CD16-deficient NK-92 cells. An association between CD16 and CD2 was identified biochemically and at the immunological synapse, which elicited CD16 signaling after CD2 engagement. Stable expression of CD16 L66H in NK-92 cells recapitulated the patient phenotype, abrogating association of CD16 with CD2 as well as CD16 signaling after CD2 ligation. Thus, CD16 serves a role in NK cell-mediated spontaneous cytotoxicity through a specific association with CD2 and represents a potential mechanism underlying a human congenital immunodeficiency.
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