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

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48 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)1721-1728
Número de páginas8
PublicaciónJournal of Immunology
Volumen169
N.º4
DOI
EstadoPublished - ago. 15 2002
Publicado de forma externa

ASJC Scopus Subject Areas

  • Immunology and Allergy
  • Immunology

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