Increased NK cell immunity in a transgenic mouse model of NKp46 overexpression

Ariella Glasner,Ofer Mandelboim,Sergey Viukov,Veronika Sexl,Jacob H Hanna,Nehemya Friedman,Batya Isaacson,Michal Mandelboim,Tzahi Neuman

doi:10.1038/s41598-017-12998-w

Abstract

Natural Killer (NK) cells employ activating receptors like the Natural Cytotoxicity Receptors (NCRs: NKp30, NKp44 and NKp46), of which only NKp46 has a mouse orthologue (Ncr1), to eliminate abnormal cells. NKp46/Ncr1 is considered a selective marker for NK cells, although it is also found on a subset of ILCs, where it appears to be without function. The influenza virus hemagglutinin (HA) was the first ligand identified for Ncr1/NKp46 followed by other viral, bacterial and even fungal ligands. NKp46/Ncr1 also recognizes unknown self and tumor ligands. Here we describe the generation of a transgenic mouse where the Ncr1 gene is expressed in the Rosa locus, preceded by a floxed stop sequence allowing Ncr1/NKp46 expression in various tissues upon crossing with Cre transgenic mouse lines. Surprisingly, while several crossings were attempted, Ncr1 overexpression was successful only where cre recombinase expression was dependent on the Ncr1 promoter. Ncr1 overexpression in NK cells increased NK cell immunity in two hallmark Ncr1 related pathologies, influenza virus infection and B16 melanoma. These data suggest that increasing NK cell cytotoxicity by enforced NKp46/Ncr1 expression serves as a potential therapeutic opportunity for the treatment of various pathologies, and in immunotherapy.

Highlights

Natural Killer (NK) cells are important first line of defense innate lymphocytes
NKp46 activities we generated an “Ncr[1] gain of function” mouse that enables the overexpression of Ncr[1] in NK cells
The chimera offspring were bred with wild type (WT) C57BL/6 mice, and four progeny carrying Ncr[1] were selected for further breeding

Summary

Introduction

NK cells are important first line of defense innate lymphocytes They were shown to participate in many immunological and regulatory processes including viral[1,2,3,4,5,6,7,8,9,10,11], bacterial and fungal infections[12,13,14], cancer[8,9,15,16,17,18,19,20], graft versus host disease[21], autoimmunity[22,23,24], allergy[25] and pregnancy[26]. Several mice deficient for other NK activating receptors were generated, including NKG2D deficient mice[44,45], and a mouse lacking both NKG2D and NKp4646. NKp46 activities we generated an “Ncr[1] gain of function” mouse (denoted Ncr1cre Ncr1OE) that enables the overexpression of Ncr[1] in NK cells

Methods

Results

Conclusion