title: IFN-gamma-mediated negative feedback regulation of NKT-cell function by CD94/NKG2.
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 alpha-galactosylceramide (alpha-GalCer) or its analog OCH [(2S,3S,4R)-1-O-(alpha-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, alpha-GalCer was inferior to OCH in priming iNKT cells for subsequent restimulation because alpha-GalCer-induced interferon gamma (IFN-gamma) 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.
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ota
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Kouetsu
authors.initials: K
authors.lastname: Ogasawara
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ikarashi
authors.forename: Sachiko
authors.initials: S
authors.lastname: Miyake
authors.forename: Hiro
authors.initials: H
authors.lastname: Wakasugi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamura
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D025461:Feedback, Physiological / Q000502:physiology; D005699:Galactosylceramides / Q000494:pharmacology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011971:Receptors, Immunologic / Q000378:metabolism*; D055607:Receptors, Natural Killer Cell
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D005699:Galactosylceramides; D015395:Histocompatibility Antigens Class I; C527057:Klrc1 protein, mouse; C497870:Klrd1 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; C032907:Q surface antigens; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C493154:alpha-galactosylceramide; D007371:Interferon-gamma
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