Impaired natural killing of MHC class I-deficient targets by NK cells expressing a catalytically inactive form of SHP-1.


Autoria(s): Lowin-Kropf B.; Kunz B.; Beermann F.; Held W.
Data(s)

2000

Resumo

NK cell function is negatively regulated by MHC class I-specific inhibitory receptors. Transduction of the inhibitory signal involves protein tyrosine phosphatases such as SHP-1 (SH2-containing protein tyrosine phosphatase-1). To investigate the role of SHP-1 for NK cell development and function, we generated mice expressing a catalytically inactive, dominant-negative mutant of SHP-1 (dnSHP-1). In this paper we show that expression of dnSHP-1 does not affect the generation of NK cells even though MHC receptor-mediated inhibition is partially impaired. Despite this defect, these NK cells do not kill syngeneic, normal target cells. In fact dnSHP-1-expressing NK cells are hyporesponsive toward MHC-deficient target cells, suggesting that non-MHC-specific NK cell activation is significantly reduced. In contrast, these NK cells mediate Ab-dependent cell-mediated cytotoxicity and prevent the engraftment with beta2-microglobulin-deficient bone marrow cells. A similar NK cell phenotype is observed in viable motheaten (mev) mice, which show reduced SHP-1 activity due to a mutation in the Shp-1 gene. In addition, NK cells in both mouse strains show a tendency to express more inhibitory MHC-specific Ly49 receptors. Our results demonstrate the importance of SHP-1 for the generation of functional NK cells, which are able to react efficiently to the absence of MHC class I molecules from normal target cells. Therefore, SHP-1 may play an as-yet-unrecognized role in some NK cell activation pathways. Alternatively, a reduced capacity to transduce SHP-1-dependent inhibitory signals during NK cell development may be compensated by the down-modulation of NK cell triggering pathways.

Identificador

http://serval.unil.ch/?id=serval:BIB_94AB6083656A

isbn:0022-1767

pmid:10903732

isiid:000088340600020

Idioma(s)

en

Fonte

Journal of immunology, vol. 165, no. 3, pp. 1314-1321

Palavras-Chave #Animals; Antigens, Ly; Bone Marrow Transplantation/immunology; Catalysis; Cell Differentiation/genetics; Cell Differentiation/immunology; Cell Line; Crosses, Genetic; Cytotoxicity, Immunologic/genetics; Enzyme Activation/genetics; Enzyme Activation/immunology; Graft Rejection/genetics; Graft Rejection/immunology; Histocompatibility Antigens Class I/genetics; Immunity, Innate/genetics; Intracellular Signaling Peptides and Proteins; Killer Cells, Natural/cytology; Killer Cells, Natural/enzymology; Lectins, C-Type; Membrane Glycoproteins/physiology; Mice; Mice, Mutant Strains; Mice, Transgenic; Mutagenesis, Insertional; Point Mutation; Protein Phosphatase 1; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases/biosynthesis; Protein Tyrosine Phosphatases/deficiency; Receptors, NK Cell Lectin-Like; SH2 Domain-Containing Protein Tyrosine Phosphatases; T-Lymphocytes/cytology; Tumor Cells, Cultured; beta 2-Microglobulin/deficiency; beta 2-Microglobulin/genetics; src Homology Domains/genetics; src Homology Domains/immunology
Tipo

info:eu-repo/semantics/article

article