CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells

Gabriella Palmieri, Valentino Tullio, Alessandra Zingoni, Mario Piccoli, Luigi Frati, Miguel Lopez-Botet, Angela Santoni

Research output: Contribution to journalArticle

Abstract

The CD94/NKG2-A complex is the inhibitory receptor for the nonclassical MHC class I molecule HLA-E on human NK cells. Here we studied the molecular mechanisms underlying the inhibitory activity of CD94/NKG2-A on NK cell functions by analyzing its interference on CD16-initiated signaling pathways involved in the control of cytolytic activity. Both tyrosine phosphorylation and activation of Syk kinase together with tyrosine phosphorylation of CD16 receptor ζ subunit are markedly inhibited by the coengagement of CD94/NKG2- A complex. As a downstream consequence, CD94/NKG2-A cross-linking impairs the CD16-induced activation of extracellular regulated kinases (ERKs), a pathway involved in NK cytotoxic function. The block of ERK activation is exerted at an early, PTK-dependent stage in the events leading to p21(ras) activation, as the CD16-induced tyrosine phosphorylation of Shc adaptor protein and the formation of Shc/Grb-2 complex are abrogated by CD94/NKG2-A simultaneous engagement. Our observations indicate that CD94/NKG2-A inhibits the CD16- triggered activation of two signaling pathways involved in the cytotoxic activity of NK cells. They thus provide molecular evidence to explain the inhibitory function of CD94/NKG2-A receptor on NK effector functions.

Original languageEnglish
Pages (from-to)7181-7188
Number of pages8
JournalJournal of Immunology
Volume162
Issue number12
Publication statusPublished - Jun 15 1999

ASJC Scopus subject areas

  • Immunology

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    Palmieri, G., Tullio, V., Zingoni, A., Piccoli, M., Frati, L., Lopez-Botet, M., & Santoni, A. (1999). CD94/NKG2-A inhibitory complex blocks CD16-triggered Syk and extracellular regulated kinase activation, leading to cytotoxic function of human NK cells. Journal of Immunology, 162(12), 7181-7188.