Aberrant DAP12 signaling in the 129 strain of mice: Implications for the analysis of gene-targeted mice

Daniel W. McVicar, Robin Winkler-Pickett, Lynn S. Taylor, Andrew Makrigiannis, Michael Bennett, Stephen K. Anderson, John R. Ortaldo

Résultat de recherche: Articleexamen par les pairs

48 Citations (Scopus)

Résumé

NK cells are implicated in antiviral responses, bone marrow transplantation and tumor immunosurveillance. Their function is controlled, in part, through the Ly49 family of class I binding receptors. Inhibitory Ly49s suppress signaling, while activating Ly49s (i.e., Ly49D) activate NK cells via the DAP12 signaling chain. Activating Ly49 signaling has been studied primarily in C57BL/6 mice, however, 129 substrains are commonly used in gene-targeting experiments. In this study, we show that in contrast to C57BL/6 NK cells, cross-linking of DAP12-coupled receptors in 129/J mice induces phosphorylation of DAP12 but not calcium mobilization or cytokine production. Consistent with poor-activating Ly49 function, 129/J mice reject bone marrow less efficiently than C57BL/6 mice. Sequence analysis of receptors and DAP12 suggests no structural basis for inactivity, and both the 129/J and C57BL/6 receptors demonstrate normal function in a reconstituted receptor system. Most importantly, reconstitution of Ly49D in 129/J NK cells demonstrated that the signaling deficit is within the NK cells themselves. These unexpected findings bring into question any NK analysis of 129/J, 129Sv, or gene-targeted mice derived from these strains before complete backcrossing, and provide a possible explanation for the differences observed in the immune response of 129 mice in a variety of models.

Langue d'origineEnglish
Pages (de-à)1721-1728
Nombre de pages8
JournalJournal of Immunology
Volume169
Numéro de publication4
DOI
Statut de publicationPublished - août 15 2002
Publié à l'externeOui

ASJC Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

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