Brigl, M. et al. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J. Exp. Med. 208, 1163-1177

Department of Pathology, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/2011; 208(6):1163-77. DOI: 10.1084/jem.20102555
Source: PubMed


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.

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    • "In contrast to the mDCs, pDCs lack the expression of CD1d, which is an important molecule for crosstalk with iNKT cells (105). Nonetheless, over the past few years the ability of iNKT cell to “sense” subtle changes within their microenvironment in a CD1d-independent mechanism, uncovered that cytokines released by pDCs are essential (106, 107). Indeed, CpG activated pDCs upregulate activation markers on iNKT cells via TNF-α and IFN-α release, and selectively enhance double-negative iNKT cell survival but not that of other NKT cell populations (104). "
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    • "Many PLZF-regulated genes from our analysis were differentially expressed between iNKT and CD4+ thymocytes (Figure 1C), consistent with our gene set representing the NKT molecular program. Since Id2 (Monticelli et al., 2009), c-Maf (Kim et al., 1999), as well as ICOS (Akbari et al., 2008; Chung et al., 2008; Watanabe et al., 2010), IL12R (Brigl et al., 2003, 2011), and IL18R (Nagarajan and Kronenberg, 2007; Velazquez et al., 2008) signaling pathways had previously been implicated in NKT cell development, homeostasis and/or function, we proceeded to validate these targets in iNKT and γδNKT cells from wt and PLZF-deficient mice that did not express TCR transgenes. "
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