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

Lampe K, Endale M, Cashman S, Fang H, Mattner J, Hildeman D, Hoebe K (2015)

Publication Type: Journal article

Publication year: 2015

Journal

European Journal of Immunology Wiley-VCH Verlag

Book Volume: 45

Pages Range: 2072-83

Journal Issue: 7

DOI: 10.1002/eji.201445352

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 ?2-microglobulin (?2M) 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-?2M(-/-) 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 with CRIS profile

Jochen Mattner Professur für Medizinische Mikrobiologie und Infektionsimmunologie

Involved external institutions

Cincinnati Children's Hospital Medical Center US United States (USA) (US) University of Oxford GB United Kingdom (GB)

How to cite

APA:

Lampe, K., Endale, M., Cashman, S., Fang, H., Mattner, J., Hildeman, D., & Hoebe, K. (2015). Slp-76 is a critical determinant of NK-cell mediated recognition of missing-self targets. European Journal of Immunology, 45(7), 2072-83. https://doi.org/10.1002/eji.201445352

MLA:

Lampe, Kristin, et al. "Slp-76 is a critical determinant of NK-cell mediated recognition of missing-self targets." European Journal of Immunology 45.7 (2015): 2072-83.

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