CD3ζ adaptor structure determines functional differences between human and mouse CD16 Fc-gamma receptor signaling in natural killer cells

• Published in: The Journal of immunology (1950) Vol. 208; no. 1_Supplement; pp. 164 - 164.04
• Main Authors: Aguilar, Oscar A, Fong, Lam-Kiu, Ishiyama, Kenichi, DeGrado, William F, Lanier, Lewis L
• Format: Journal Article
• Language: English
• Published: 01.05.2022
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.208.Supp.164.04

Abstract Natural killer (NK) cells are innate lymphocytes capable of distinguishing between healthy and pathogenic cells using a myriad of receptors expressed on their cell surface. The CD16 receptor detects the Fc portion of IgG on antibody-coated cells resulting in NK cell activation. The importance of this receptor on human NK cell biology has long been appreciated; however, how CD16 functions in mouse NK cells remains poorly understood. Here, we report drastic differences between human and mouse CD16 functions in NK cells. We demonstrate that one of the adaptor molecules that CD16 associates with and signals through, CD3ζ, plays a critical role in these functional differences. Using a systematic approach, we demonstrate that key residues in the transmembrane domain of the mouse CD3ζ molecule prevent efficient complex formation with mouse CD16, thereby dampening receptor function. Mutating these residues in mouse CD3ζ to those encoded by human CD3ζ resulted in rescue of CD16 receptor function. Supported by grants from the Cancer Research Institute (CRI), Burroughs Wellcome Fund (BWF), the Parker Institute for Cancer Immunotherapy (PICI) and NIH grants AI068129 and AI146581.