T CELLS a Killer Cytokine

RESEARCH HIGHLIGHTS S.Bradbrook/NPG T CELLS A killer cytokine T helper 17 (TH17) cells have specific for IL-26 or small interfering with live human cells. However, well-known antimicrobial and RNA against IL26. Similar to other when IL-26 was mixed with irradi- inflammatory functions, but exactly cationic antimicrobial peptides, such ated human cells to trigger cell how these functions are mediated as LL-37 and human β-defensin 3, death, IFNα production by pDCs is unclear. New research shows recombinant IL-26 was shown to was induced, and this was largely that the human TH17 cell-derived disrupt bacterial membranes by abrogated by DNase treatment. cytokine interleukin-26 (IL-26) pore formation. To investigate the mechanism of functions like an antimicrobial As LL-37 has been shown to form IFNα induction, the authors used peptide, directly lysing bacteria and complexes with extracellular DNA, fluorochrome-labelled DNA to track promoting immunogenicity of DNA the authors next tested whether this IL-26–DNA complexes in pDCs. from dead bacteria and host cells. was also the case for IL-26. Indeed, They found that the complexes were Three-dimensional modelling when mixed with bacterial DNA, internalized by pDCs through endo- of IL-26 showed that its structure is IL-26 formed insoluble particles cytosis following attachment to mem- unlike that of other cytokines from with DNA. Moreover, compared brane heparin-sulfate proteoglycans. the same family, and instead it shares with IL-26 alone or bacterial Once inside the cell, the IL-26–DNA features with antimicrobial peptides: DNA alone, IL-26–DNA com- complexes activated endosomal specifically, an amphipathic structure, plexes induced the production of Toll-like receptor 9 (TLR9), which with clusters of cationic charges, and interferon-α (IFNα) by plasmacytoid promotes IFNα production. Finally, an ability to form multimers as well as dendritic cells (pDCs). IL-26-lysed the authors showed that supernatants dimers. Tests for antimicrobial activity bacteria but not live bacteria also from cultures of TH17 cells that showed that IL-26 can directly inhibit induced strong IFNα production, contain some dead cells or exogenous IL-26 binds the growth of several Gram-negative which could be inhibited when DNA DNA induced IFNα production by and Gram-positive bacteria in vitro was depleted by DNase treatment, pDCs in an IL-26-dependent manner, bacterial DNA and can reduce bacterial titres in a suggesting that IL-26 binds bacterial providing a new explanation for the released from mouse model of Klebsiella pneumoniae DNA released from dead bacteria known association of TH17 cells with dead bacteria sepsis. In addition, supernatant from and promotes its immunogenicity. autoimmune disease. cultures of human T 17 cells but not So, what about human DNA? Lucy Bird and promotes H of T 0 cells (which do not express Recombinant IL-26 did not have its immuno- H ORIGINAL RESEARCH PAPER Meller, S. et al. IL-26) efficiently killed extracellular any direct cytotoxic activity against TH17 cells promote microbial killing and innate genicity bacteria, an effect that was abrogated human cells and did not induce IFNα immune sensing of DNA via interleukin 26. Nat. Immunol. http://dx.doi.org/10.1038/ni.3211 (2015) by the presence of blocking antibody production by pDCs when mixed NATURE REVIEWS | IMMUNOLOGY VOLUME 15 | AUGUST 2015 © 2015 Macmillan Publishers Limited. All rights reserved.

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