Distinct HLA-E Peptide Complexes Modify Antibody-Driven Effector Functions of Adaptive NK Cells.

Area of Science:

• Immunology
• Cellular Biology
• Virology

Background:

• Adaptive Natural Killer (NK) cells exhibit unique molecular and epigenetic profiles compared to canonical NK cells.
• Their development is associated with prior human cytomegalovirus (HCMV) infection, but regulatory and functional aspects require further elucidation.
• Many adaptive NK cells express CD94/NKG2C, which binds to human leukocyte antigen E (HLA-E) presenting specific peptides.

Purpose of the Study:

• To investigate the specificity of adaptive NK cell recognition of different HLA-E peptide complexes.
• To determine how prolonged exposure to specific HLA-E peptide ligands influences adaptive NK cell characteristics and functions.

Main Methods:

• Comparative analysis of adaptive NK cells exposed to various HLA-E peptide ligands.
• Assessment of FcεRγ and CD25 expression levels.
• Evaluation of proliferative activity, antibody-dependent cellular cytotoxicity (ADCC), and interferon-gamma (IFN-γ) production.

Main Results:

• Adaptive NK cells demonstrated exquisite specificity in discriminating between HLA-E-peptide complexes.
• Exposure to the HLA-E peptide ligand VMAPRTLFL (derived from HLA-G) enriched adaptive NK cells with low FcεRγ and high CD25 expression.
• This specific ligand exposure led to increased proliferation, enhanced ADCC, and elevated IFN-γ responses compared to other HLA-E peptide complexes.

Conclusions:

• Recognition of alterations in the HLA-E ligandome by activating receptors can modulate adaptive NK cell effector mechanisms.
• Specific HLA-E peptide recognition influences adaptive NK cell proliferation and cytotoxic functions, highlighting a novel regulatory pathway.