TY - JOUR
T1 - IFN-γ-mediated negative feedback regulation of NKT-cell function by CD94/NKG2
AU - Ota, Tsuyoshi
AU - Takeda, Kazuyoshi
AU - Akiba, Hisaya
AU - Hayakawa, Yoshihiro
AU - Ogasawara, Kouetsu
AU - Ikarashi, Yoshinori
AU - Miyake, Sachiko
AU - Wakasugi, Hiro
AU - Yamamura, Takashi
AU - Kronenberg, Mitchell
AU - Raulet, David H.
AU - Kinoshita, Katsuyuki
AU - Yagita, Hideo
AU - Smyth, Mark J.
AU - Okumura, Ko
PY - 2005/7/1
Y1 - 2005/7/1
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2004-11-4257
DO - 10.1182/blood-2004-11-4257
M3 - Article
C2 - 15746081
AN - SCOPUS:22044454987
VL - 106
SP - 184
EP - 192
JO - Blood
JF - Blood
SN - 0006-4971
IS - 1
ER -