Type I Natural Killer T Cells Suppress Infection-Induced Hypercytokinemia via an IL-22-Dependent Mechanism

Torres et al., bioRxiv (preprint), 2026 asked which subset of natural killer T cells governs the cytokine storm that follows severe bacterial infection, and by what molecule. Working with Francisella tularensis subsp. holarctica LVS in mice, the authors found that type I natural killer T cells act as the dominant suppressors of hyperinflammation after intradermal infection, while type II cells give little protection. Purified natural killer T cells added to infected macrophages cut IL-1 beta and IL-6 production by 85-95%, and the effect survived transfer of cell-free supernatant but not fixation of the cells, which pointed to a secreted mediator.

That mediator proved to be IL-22. Neutralising IL-22 abolished the suppression, and recombinant IL-22 reproduced it with no natural killer T cells present. Because macrophages can also make IL-22, the authors needed to know which cell was the source, and this is where the AUM product enters. Self-delivering AUMsilence sdASOs against IL-22, two of them, were added to macrophages at 10 μM overnight with no transfection reagent and washed off before infection. They stopped stimulated macrophages producing IL-22.

Pre-treated macrophages still received IL-22 from the co-cultured type I natural killer T cells, and IL-6 suppression was unaffected, so the active IL-22 came from the natural killer T cells. The authors also record that they tried the same silencing in the purified natural killer T cells and could not, because the oligonucleotides were toxic to those cells while the macrophages tolerated them. Downstream, type I natural killer T cells drove STAT3 phosphorylation in macrophages and induced the STAT3 responsive genes IL-1Rn, Socs3, Cish and TNFaip3.