Slp‐76 is a critical determinant of NK‐cell mediated recognition of missing‐self targets. Issue 7 (22nd May 2015)

• Record Type: Journal Article
• Authors: Lampe, Kristin; Endale, Mehari; Cashman, Siobhan; Fang, Hao; Mattner, Jochen; Hildeman, David; Hoebe, Kasper
• Is Part Of: European journal of immunology. Volume 45:Issue 7(2015:Jul.)
• Page Start: 2072
• Page End: 2083
• Publication Date: 2015-05-22
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201445352
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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‐<italic>N</italic>‐nitrosourea mutagenesis in mice, we identified a germline mutant, designated <italic>Ace</italic>, 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 <italic>Ace</italic> 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 <italic>Slp‐76<sup>ace/ace</sup></italic> NK cells through ITAM‐containing NK‐cell receptors or allogeneic/tumor target cells appeared largely unaffected. Imagestream analysis of the NK‐β2M<sup>−/−</sup> target cell synapse revealed a specific defect in actin recruitment to the conjugate synapse in <italic>Slp‐76<sup>ace/ace</sup></italic> 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.</p> </abstract>