Controlling natural killer cell responses: Integration of signals for activation and inhibition

Eric O. Long, Hun Sik Kim, Dongfang Liu, Mary E. Peterson, Sumati Rajagopalan

Research output: Contribution to journalReview articlepeer-review

781 Scopus citations


Understanding how signals are integrated to control natural killer (NK) cell responsiveness in the absence of antigen-specific receptors has been a challenge, but recent work has revealed some underlying principles that govern NK cell responses. NK cells use an array of innate receptors to sense their environment and respond to alterations caused by infections, cellular stress, and transformation. No single activation receptor dominates; instead, synergistic signals from combinations of receptors are integrated to activate natural cytotoxicity and cytokine production. Inhibitory receptors for major histocompatibility complex class I (MHC-I) have a critical role in controlling NK cell responses and, paradoxically, in maintaining NK cells in a state of responsiveness to subsequent activation events, a process referred to as licensing. MHC-I-specific inhibitory receptors both block activation signals and trigger signals to phosphorylate and inactivate the small adaptor Crk. These different facets of inhibitory signaling are incorporated into a revocable license model for the reversible tuning of NK cell responsiveness.

Original languageEnglish (US)
Pages (from-to)227-258
Number of pages32
JournalAnnual Review of Immunology
StatePublished - Mar 2013


  • Inhibitory receptor
  • Licensing
  • Major histocompatibility complex
  • Signaling

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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