Slp-76 is a critical determinant of NK-cell mediated recognition of missing-self targets.
Absence of MHC class I expression is an important mechanism by which NK cells recognize a variety of target cells, yet the pathways underlying "missing-self" recognition, including the involvement of activating receptors, remain poorly understood. Using ethyl-N-nitrosourea mutagenesis in mice, we identified a germline mutant, designated Ace, with a marked defect in NK cell mediated recognition and elimination of "missing-self" targets. The causative mutation was linked to chromosome 11 and identified as a missense mutation (Thr428Ile) in the SH2 domain of Slp-76-a critical adapter molecule downstream of ITAM-containing surface receptors. The Slp-76 Ace mutation behaved as a hypomorphic allele-while no major defects were observed in conventional T-cell development/function, a marked defect in NK cell mediated elimination of β2-microglobulin (β2M) deficient target cells was observed. Further studies revealed Slp-76 to control NK-cell receptor expression and maturation; however, activation of Slp-76(ace/ace) NK cells through ITAM-containing NK-cell receptors or allogeneic/tumor target cells appeared largely unaffected. Imagestream analysis of the NK-β2M(-/-) target cell synapse revealed a specific defect in actin recruitment to the conjugate synapse in Slp-76(ace/ace) NK cells. Overall these studies establish Slp-76 as a critical determinant of NK-cell development and NK cell mediated elimination of missing-self target cells in mice.
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
Kristin
K
Lampe
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
Mehari
M
Endale
Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Siobhan
S
Cashman
Division of Infectious Diseases, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
Hao
H
Fang
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Jochen
J
Mattner
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
David
D
Hildeman
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
Kasper
K
Hoebe
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D005434:Flow Cytometry; D015151:Immunoblotting; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins
Cytotoxicity; Innate immunity; NK cells; Self/nonself discrimination; Signal transduction