(Auto)Antibody Responses Shape Memory NK Cell Pool Size and Composition

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Human cytomegalovirus (HCMV) infection induces adaptive immune responses, including the formation of memory Natural Killer (NK) cells.
• Memory NK cells are characterized by Fc receptor gamma (FcεRIγ) deficiency and expression of NKG2C and CD57.
• The role of CD16-mediated antibody signaling in shaping memory NK cell populations remains incompletely understood.

Purpose of the Study:

• To investigate the ex vivo profile and in vitro responsiveness of memory NK cells to CD16 stimulation in HCMV-positive donors and immune thrombocytopenia (ITP) patients.
• To determine the impact of opsonizing antibodies on the establishment and expansion of memory NK cell subsets.

Main Methods:

• Flow cytometry analysis of NK cell subsets (FcεRIγ-, NKG2C+, CD57+) in healthy HCMV+ donors and ITP patients.
• In vitro expansion assays using antibody-opsonized targets and ITP-derived platelets.
• Assessment of CD16-dependent Interferon-gamma (IFNγ) production.

Main Results:

• A specific FcεRIγ- NKG2C+CD57+ memory NK cell subset was identified, with abundance correlating with anti-HCMV antibody levels in healthy individuals.
• This memory NK cell subset was significantly expanded in ITP patients, an antibody-mediated autoimmune disease.
• These cells demonstrated robust and selective in vitro expansion upon stimulation with antibody-opsonized targets or ITP platelets, exhibiting superior CD16-dependent IFNγ production.

Conclusions:

• Opsonizing antibodies are a critical host-dependent factor shaping the HCMV-driven memory NK cell compartment.
• Chronic exposure to auto-antibodies contributes to the expansion of a specialized memory NK cell subset with distinct CD16-dependent functions.
• The absence of the FcεRIγ chain confers enhanced responsiveness to CD16 engagement in NKG2C+CD57+ memory NK cells.