IFN-γ-mediated negative feedback regulation of NKT-cell function by CD94/NKG2

Tsuyoshi Ota, Kazuyoshi Takeda, Hisaya Akiba, Yoshihiro Hayakawa, Kouetsu Ogasawara, Yoshinori Ikarashi, Sachiko Miyake, Hiro Wakasugi, Takashi Yamamura, Mitchell Kronenberg, David H. Raulet, Katsuyuki Kinoshita, Hideo Yagita, Mark J. Smyth, Ko Okumura

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

Activation of invariant natural killer T (iNKT) cells with CD1d-restricted T-cell receptor (TCR) ligands is a powerful means to modulate various immune responses. However, the iNKT-cell response is of limited duration and iNKT cells appear refractory to secondary stimulation. Here we show that the CD94/NKG2A inhibitory receptor plays a critical role in down-regulating iNKT-cell responses. Both TCR and NK-cell receptors expressed by iNKT cells were rapidly down-modulated by priming with a-galactosylceramide (α-GalCer) or its analog OCH [(2S,3S,4R)-1-O-(α-D-galactopyranosyl)-N-tetracosanoyl-2-amino- 1,3,4-nonanetriol)]. TCR and CD28 were re-expressed more rapidly than the inhibitory NK-cell receptors CD94/NKG2A and Ly49, temporally rendering the primed iNKT cells hyperreactive to ligand restimulation. Of interest, α-GalCer was inferior to OCH in priming iNKT cells for subsequent restimulation because α-GalCer-induced interferon γ (IFN-γ) up-regulated Qa-1b expression and Qa-1b in turn inhibited iNKT-cell activity via its interaction with the inhibitory CD94/ NKG2A receptor. Blockade of the CD94/ NKG2-Qa-1b interaction markedly augmented recall and primary responses of iNKT cells. This is the first report to show the critical role for NK-cell receptors in controlling iNKT-cell responses and provides a novel strategy to augment the therapeutic effect of iNKT cells by priming with OCH or blocking of the CD94/ NKG2A inhibitory pathway in clinical applications.

Original languageEnglish
Pages (from-to)184-192
Number of pages9
JournalBlood
Volume106
Issue number1
DOIs
Publication statusPublished - 2005 Jul 1

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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