Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells

Kamalakannan Rajasekaran, Pawan Kumar, Kristina M. Schuldt, Erik J. Peterson, Bart Vanhaesebroeck, Vishva Dixit, Monica S. Thakar, Subramaniam Malarkannan

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma and various autoimmune disorders. Here we identified a signaling pathway that was exclusively responsible for the production of inflammatory cytokines but not for cytotoxicity. Recognition of tumor cells expressing the NK cell-activatory ligands H60 or CD137L by mouse natural killer (NK) cells led to efficient cytotoxicity and the production of inflammatory cytokines. Both of those effector functions required the kinases Lck, Fyn and PI(3)K (subunits p85α and p110δ) and the signaling protein PLC-γ2. However, a complex of Fyn and the adaptor ADAP exclusively regulated the production of inflammatory cytokines but not cytotoxicity in NK cells. That unique function of ADAP required a Carma1-Bcl-10-MAP3K7 signaling axis. Our results have identified molecules that can be targeted to regulate inflammation without compromising NK cell cytotoxicity.

Original languageEnglish (US)
Pages (from-to)1127-1136
Number of pages10
JournalNature immunology
Volume14
Issue number11
DOIs
StatePublished - 2013

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