title: Expression of NKp46 Splice Variants in Nasal Lavage Following Respiratory Viral Infection: Domain 1-Negative Isoforms Predominate and Manifest Higher Activity.
abstract: The natural killer (NK) cell activating receptor NKp46/NCR1 plays a critical role in elimination of virus-infected and tumor cells. TheNCR1gene can be transcribed into five different splice variants, but the functional importance and physiological distribution of NKp46 isoforms are not yet fully understood. Here, we shed light on differential expression of NKp46 splice variants in viral respiratory tract infections and their functional difference at the cellular level. NKp46 was the most predominantly expressed natural cytotoxicity receptor in the nasal lavage of patients infected with four respiratory viruses: respiratory syncytia virus, adenovirus, human metapneumovirus, or influenza A. Expression of NKp30 was far lower and NKp44 was absent in all patients. Domain 1-negative NKp46 splice variants (i.e., NKp46 isoform d) were the predominantly expressed isoform in nasal lavage following viral infections. Using our unique anti-NKp46 mAb, D2-9A5, which recognizes the D2 extracellular domain, and a commercial anti-NKp46 mAb, 9E2, which recognizes D1 domain, allowed us to identify a small subset of NKp46 D1-negative splice variant-expressing cells within cultured human primary NK cells. This NKp46 D1-negative subset also showed higher degranulation efficiency in term of CD107a surface expression. NK-92 cell lines expressing NKp46 D1-negative and NKp46 D1-positive splice variants also showed functional differences when interacting with targets. A NKp46 D1-negative isoform-expressing NK-92 cell line showed enhanced degranulation activity. To our knowledge, we provide the first evidence showing the physiological distribution and functional importance of human NKp46 splice variants under pathological conditions.
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva , Israel.
authors.forename: Yonat
authors.initials: Y
authors.lastname: Shemer-Avni
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Kiran
authors.initials: K
authors.lastname: Kundu
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Avishai
authors.initials: A
authors.lastname: Shemesh
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva , Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Brusilovsky
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva , Israel.
authors.forename: Rami
authors.initials: R
authors.lastname: Yossef
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva , Israel.
authors.forename: Mesfin
authors.initials: M
authors.lastname: Meshesha
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva , Israel.
authors.forename: Semaria
authors.initials: S
authors.lastname: Solomon-Alemayehu
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva , Israel.
authors.forename: Shai
authors.initials: S
authors.lastname: Levin
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva , Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Gershoni-Yahalom
authors.affiliation: Institute for Cancer Research, Fox Chase Cancer Center , Philadelphia, PA , USA.
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Campbell
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel; National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Angel
authors.initials: A
authors.lastname: Porgador
keywords: NCR; NKp46; natural killer; respiratory viral infection; splice variants