Open Access

Francisca F. Almeida, Sara Tognarelli, Antoine Marçais, Andrew J. Kueh, Miriam Elisabeth Friede, Yang Liao, Simon N. Willis, Kylie Luong, Fabrice Faure, Francois E. Mercier, Justine Galluso, Matthew Firth, Emilie Narni-Mancinelli, Bushra Rais, David T. Scadden, Francesco Spallotta, Sandra Weil, Ariane Giannattasio, Franziska Kalensee, Tobias Zöller, Nicholas D. Huntington, Ulrike Schleicher, Andreas Geburtig-Chiocchetti, Sophie Ugolini, Marco Herold, Wei Shi, Joachim Koch, Alexander Steinle, Eric Vivier, Thierry Walzer, Gabrielle T. Belz, Evelyn Ullrich

• NKp46 (CD335) is a surface receptor shared by both human and mouse natural killer (NK) cells and innate lymphoid cells (ILCs) that transduces activating signals necessary to eliminate virus-infected cells and tumors. Here, we describe a spontaneous point mutation of cysteine to arginine (C14R) in the signal peptide of the NKp46 protein in congenic Ly5.1 mice and the newly generated NCRB6C14R strain. Ly5.1C14R NK cells expressed similar levels of Ncr1 mRNA as C57BL/6, but showed impaired surface NKp46 and reduced ability to control melanoma tumors in vivo. Expression of the mutant NKp46C14R in 293T cells showed that NKp46 protein trafficking to the cell surface was compromised. Although Ly5.1C14R mice had normal number of NK cells, they showed an increased number of early maturation stage NK cells. CD49a+ILC1s were also increased but these cells lacked the expression of TRAIL. ILC3s that expressed NKp46 were not detectable and were not apparent when examined by T-bet expression. Thus, the C14R mutation reveals that NKp46 is important for NK cell and ILC differentiation, maturation and function.