Spatially restricted regulation of cell competition by the cytokine Spaetzle

Growing tissues are communities of cells that cooperate to form a robust, functional organ. Cooperative behavior is enforced by cell competition, wherein comparisons of fitness lead to selective elimination of cells sensed as relatively less healthy. Elimination of these ‘loser’ cells from Drosophila wing imaginal discs results in cell death induced by deployment of a genetic module consisting of the secreted Toll ligand Spätzle (Spz), several Toll related receptors, and NFkB factors. How signaling by this module is activated and restricted only to competing cells is unknown. Here, we investigate the signaling role of Spz in Myc-induced cell competition. We demonstrate that elimination of wild-type loser cells requires local synthesis and activation of Spz in the wing disc. We identify Spätzle Processing Enzyme (SPE) and Modular Serine Protease (modSP) as upstream mediators of Spz-mediated loser cell elimination, and show that an increase in SPE in ‘winner’ cells is required for Spz to kill loser cells. Finally, we show that Spz requires both Toll and Toll-8 to induce apoptosis of wing disc cells. Our results indicate that during cell competition, Spz-mediated signaling is strictly confined to the imaginal disc, allowing errors in tissue fitness to be corrected without compromising organismal physiology.