Slp-76 is a critical determinant of NK-cell mediated recognition of missing-self targets.

Abstract

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.

• Authors: Kristin Lampe, Mehari Endale, Siobhan Cashman, Hao Fang, Jochen Mattner, David Hildeman, Kasper Hoebe
• Journal: European journal of immunology (Eur J Immunol) Vol. 45 Issue 7 Pg. 2072-83 (Jul 2015) ISSN: 1521-4141 [Electronic] Germany
• PMID: 25929249 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Adaptor Proteins, Signal Transducing
• Phosphoproteins
• SLP-76 signal Transducing adaptor proteins

Topics

• Adaptor Proteins, Signal Transducing (immunology)
• Animals
• Flow Cytometry
• Immunoblotting
• Killer Cells, Natural (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Phosphoproteins (immunology)
• Self Tolerance (immunology)