Natural killer T-cell autoreactivity leads to a specialized activation state.
Natural killer T (NKT) cells are innate-like T cells that recognize specific microbial antigens and also display autoreactivity to self-antigens. The nature of NKT-cell autoreactive activation remains poorly understood. We show here that the mitogen-activated protein kinase (MAPK) pathway is operative during human NKT-cell autoreactive activation, but calcium signaling is severely impaired. This results in a response that is biased toward granulocyte macrophage colony-stimulating factor (GM-CSF) secretion because this cytokine requires extracellular signal-regulated kinase (ERK) signaling but is not highly calcium dependent, whereas interferon-gamma (IFN-gamma), interleukin (IL)-4, and IL-2 production are minimal. Autoreactive activation was associated with reduced migration velocity but did not induce arrest; thus, NKT cells retained the ability to survey antigen presenting cells (APCs). IL-12 and IL-18 stimulated autoreactively activated NKT cells to secrete IFN-gamma, and this was mediated by Janus kinase-signal transducers and activators of transcription (JAK-STAT)-dependent signaling without induction of calcium flux. This pathway did not require concurrent contact with CD1d(+) APCs but was strictly dependent on preceding autoreactive stimulation that induced ERK activation. In contrast, NKT-cell responses to the glycolipid antigen alpha-galactosyl ceramide (alpha-GalCer) were dampened by prior autoreactive activation. These results show that NKT-cell autoreactivity induces restricted cytokine secretion and leads to altered basal activation that potentiates innate responsiveness to costimulatory cytokines while modulating sensitivity to foreign antigens.
Wang
Xiaohua
X
Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, USA.
Chen
Xiuxu
X
Rodenkirch
Lance
L
Simonson
William
W
Wernimont
Sarah
S
Ndonye
Rachel M
RM
Veerapen
Natacha
N
Gibson
Darren
D
Howell
Amy R
AR
Besra
Gurdyal S
GS
Painter
Gavin F
GF
Huttenlocher
Anna
A
Gumperz
Jenny E
JE
D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D055610:Antigens, CD1d / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000502:physiology; D016207:Cytokines / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D005699:Galactosylceramides / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D053612:Janus Kinases / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000276:immunology*; D050791:STAT Transcription Factors / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D055610:Antigens, CD1d; D001324:Autoantigens; C526877:CD1D protein, human; D016207:Cytokines; D005699:Galactosylceramides; D050791:STAT Transcription Factors; D053612:Janus Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
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