Regulation of Cytokine Secretion in Human CD127(+) LTi-like Innate Lymphoid Cells by Toll-like Receptor 2

Department of Immunology, Genentech, South San Francisco, CA 94080, USA.
Immunity (Impact Factor: 21.56). 11/2010; 33(5):752-64. DOI: 10.1016/j.immuni.2010.10.012
Source: PubMed


Lymphoid tissue inducer cells are members of an emerging family of innate lymphoid cells (ILC). Although these cells were originally reported to produce cytokines such as interleukin-17 (IL-17) and IL-22, we demonstrate here that human CD127(+)RORC(+) and CD56(+)CD127(+) LTi-like ILC also express IL-2, IL-5, and IL-13 after activation with physiologic stimuli such as common γ-chain cytokines, Toll-like receptor (TLR) 2 ligands, or IL-23. Whereas TLR2 signaling induced IL-5, IL-13, and IL-22 expression in a nuclear factor κB (NF-κB)-dependent manner, IL-23 costimulation induced only IL-22 production. CD127(+) LTi-like ILC displayed clonal heterogeneity for IL-13 and IL-5 production, suggesting in vivo polarization. Finally, we identified a role for autocrine IL-2 signaling in mediating the effects of TLR2 stimulation on CD56(+)CD127(+) and CD127(+) LTi-like ILC. These results indicate that human LTi-like ILC can directly sense bacterial components and unravel a previously unrecognized functional heterogeneity among this important population of innate lymphoid cells.

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Available from: James P Di Santo, Sep 23, 2015
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    • "RORgt-expressing CD127 + group 3 ILCs are involved in organizing tertiary lymphoid structures (van de Pavert and Mebius, 2010), are critical in controlling containment of commensals (Sonnenberg et al., 2012), and also promote antimicrobial peptide production and the proliferation of epithelial cells (Cella et al., 2009; Crellin et al., 2010). Furthermore, IL-22 producing group 3 ILCs protect against certain bacterial pathogens such as Citrobacter rodentium, which is used as a model in mice for the attaching and effacing enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) (Satoh-Takayama et al., 2008; Sonnenberg et al., 2011). "
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    • "Indeed, inhibition of IL-12p40 (ustekinumab), the common receptor subunit of IL-12 and IL-23, is effective in treating CD [72]. ILCs can directly sense bacteria (at least through TLR2 [73]) to induce their effector functions; however , their most potent effector functions are stimulated by sensing the production of IL-23 by macrophages and DCs activated in response to microbial stimulation [57]. An essential function of ILCs is the production of IL-22. "
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    • "Another possibility is that AhR-dependent modulation of ILCs3 function is mediated by bacterial metabolites, as, under conditions of unrestricted tryptophan availability, Lactobacilli species produce indole-3-aldehyde, an AhR ligand, which enhances IL-22 expression in ILCs3 [43]. Interestingly, human ILCs3 express also RNA transcripts of Toll-like receptors (TLR) 1, 2, 5, 6, 7, and 9, though it seems that only TLR2 agonists induce cytokine production by human ILC3 in the presence of IL-2, IL-15, and IL-23 [44], supporting the hypothesis that bacteria can directly stimulate ILCs3 to synthesize effector cytokines. "
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