Innate and cytokine-driven signals, rather than microbial antigens dominate in natural killer T cell activation during microbial infection

Manfred Brigl, Raju V.V. Tatituri, Gerald F.M. Watts, Veemal Bhowruth, Elizabeth A. Leadbetter, Nathaniel Barton, Nadia R. Cohen, Fong Fu Hsu, Gurdyal S. Besra, Michael B. Brenner

Research output: Contribution to journalArticlepeer-review

195 Scopus citations

Abstract

Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological α-galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection. However, when we compared the role of microbial antigens versus innate cytokine-driven mechanisms, we found that iNKT cell interferon-γ production after in vitro stimulation or infection with diverse bacteria overwhelmingly depended on toll-like receptor-driven IL-12. Importantly, activation of iNKT cells in vivo during infection with Sphingomonas yanoikuyae or Streptococcus pneumoniae, pathogens which are known to express iNKT cell antigens and which require iNKT cells for effective protection, also predominantly depended on IL-12. Constitutive expression of high levels of IL-12 receptor by iNKT cells enabled instant IL-12-induced STAT4 activation, demonstrating that among T cells, iNKT cells are uniquely equipped for immediate, cytokine-driven activation. These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections.

Original languageEnglish (US)
Pages (from-to)1163-1177
Number of pages15
JournalJournal of Experimental Medicine
Volume208
Issue number6
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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