Natural killer T-cell autoreactivity leads to a specialized activation state

Xiaohua Wang, Xiuxu Chen, Lance Rodenkirch, William Simonson, Sarah Wernimont, Rachel M. Ndonye, Natacha Veerapen, Darren Gibson, Amy R. Howell, Gurdyal S. Besra, Gavin F. Painter, Anna Huttenlocher, Jenny E. Gumperz

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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 mitogenactivated 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 signalregulated kinase (ERK) signaling but is not highly calcium dependent, whereas interferon-γ (IFN-γ), 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-γ, 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 α-galactosyl ceramide (α-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.

Original languageEnglish (US)
Pages (from-to)4128-4138
Number of pages11
JournalBlood
Volume112
Issue number10
DOIs
StatePublished - Nov 15 2008
Externally publishedYes

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