Inhibition of selective signaling events in natural killer cells recognizing major histocompatibility complex class I

Dan S. Kaufman, Renee A. Schoon, Michael Robertson, Paul J. Leibson

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Many studies have characterized the transmembrane signaling events initiated after T-cell antigen receptor recognition of major histocompatibility complex (MHC)-bound peptides. Yet, little is known about signal transduction from a set of MHC class I recognizing receptors on natural killer (NK) cells whose ligation dramatically inhibits NK cell- mediated killing. In this study we evaluated the influence of MHC recognition on the proximal signaling events in NK cells binding tumor targets. We utilized two experimental models where NK cell-mediated cytotoxicity was fully inhibited by the recognition of specific MHC class I molecules. NK cell binding to either class I-deficient or class I-transfected target cells initiated rapid protein tyrosine kinase activation. In contrast, whereas NK cell binding to class I-deficient targets led to inositol phosphate release and increased intracellular free calcium ([Ca2+](i)), NK recognition of class I-bearing targets did not induce the activation of these phospholipase C-dependent signaling events. The recognition of class I by NK cells clearly had a negative regulatory effect since blocking this interaction using anti- class I F(ab')2 fragments increased inositol 1,4,5-trisphosphate release and [Ca2+](i) and increased the lysis of the targets. These results suggest that one of the mechanisms by which NK cell recognition of specific MHC class I molecules can block the development of cell-mediated cytotoxicity is by inhibiting specific critical signaling events.

Original languageEnglish (US)
Pages (from-to)6484-6488
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number14
DOIs
StatePublished - Jul 3 1995
Externally publishedYes

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Major Histocompatibility Complex
Natural Killer Cells
Natural Killer Cell Receptors
Inositol 1,4,5-Trisphosphate
Inositol Phosphates
Type C Phospholipases
T-Cell Antigen Receptor
Protein-Tyrosine Kinases
Ligation
Signal Transduction
Theoretical Models
Calcium
Peptides
Neoplasms

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Inhibition of selective signaling events in natural killer cells recognizing major histocompatibility complex class I. / Kaufman, Dan S.; Schoon, Renee A.; Robertson, Michael; Leibson, Paul J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 92, No. 14, 03.07.1995, p. 6484-6488.

Research output: Contribution to journalArticle

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