Research Article

An ancient defense system eliminates unfit cells from developing tissues during cell competition

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Science  05 Dec 2014:
Vol. 346, Issue 6214, 1258236
DOI: 10.1126/science.1258236

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Structured Abstract


The function of a tissue and, therefore, the health of an organism can be compromised by the presence of mutant or unfit cells. Cell competition is a mechanism that has evolved to prevent such cells from contributing to tissues. Two widely studied models of cell competition are Myc-induced supercompetition, whereby cells with increased levels of Myc outcompete and actively kill neighboring wild-type cells, and competition in which wild-type cells eliminate cells carrying a Minute mutation, a class of mutants in Drosophila affecting ribosomal protein genes. Minute cells are viable, but when surrounded by wild-type cells they are eliminated by apoptosis. Relative cell vigor or fitness is believed to be a critical feature assessed in cell competition, but the mechanisms that underlie the recognition and elimination of the less-fit “loser” cell remain mysterious.

Embedded Image

TRR/NFκB modules mediate the elimination of loser cells in two distinct contexts of cell competition. (Top) The relatively less-fit cells in mosaic tissues (green) are eliminated via cell competition. (Bottom) The competitive context influences the TRR/NFκB signaling module that is triggered in the loser cells. This module then selectively activates a proapoptotic inducer that kills the loser cells.


The recognition and elimination of unfit or mutant cells in cell competition is reminiscent of the detection of pathogens by the innate immune system. In Drosophila, the Toll and immune deficiency (IMD) signaling pathways govern the innate immune response to a broad range of pathogens and activate the NFκB transcription factor homologs Relish (Rel), Dorsal (dl), or Dorsal-related immunity factor (Dif). The conceptual similarities between innate immunity and cell competition led us to investigate whether the Toll and IMD pathways were required for cell competition in Drosophila wing discs.


Analysis of both Myc-induced and Minute-induced cell competition revealed requirements for two related but distinct cohorts of components from the IMD and Toll pathways. Both signaling cohorts required the extracellular ligand Spätzle and noncanonical Toll-related receptors (TRRs) and led to elimination of the less-fit loser cells by inducing NFκB-dependent activation of proapoptotic genes. However, our analysis uncovered interesting differences between the signaling module deployed in each competitive context. In Myc-induced competition, elimination of wild-type loser cells required four of the nine TRRs encoded in the Drosophila genome (Toll-2, Toll-3, Toll-8, and Toll-9) in nonredundant roles. By contrast, elimination of RpL14–/+ cells in Minute-induced competition required only Toll-3 and Toll-9. Furthermore, the NFκB factor activated downstream of the TRRs was also context-dependent. Signal transduction within wild-type loser cells led to selective activation of Relish, whereas the death of RpL14–/+ loser cells in Minute-induced competition required Dorsal and Dif. These results suggest that signaling from the different TRR subsets influenced which NFκB factor was activated. Finally, although in each competitive context apoptosis of the relatively less-fit cells was induced, the specific death-inducing gene expressed was determined by specifically activated NFκB factor.


In two genetically distinct contexts of cell competition, the ancient innate immune defense response system is activated and drives the elimination of the cells perceived as relatively less fit. In each competition paradigm, different signaling modules are employed, suggesting that the genetic identity of the competing cell populations influences the pathway that is activated. Our results thus provide evidence for evolutionary adaptation of TRR-NFκB signaling modules in an organismal surveillance system that measures internal tissue fitness rather than external pathogenic stimuli.


Developing tissues that contain mutant or compromised cells present risks to animal health. Accordingly, the appearance of a population of suboptimal cells in a tissue elicits cellular interactions that prevent their contribution to the adult. Here we report that this quality control process, cell competition, uses specific components of the evolutionarily ancient and conserved innate immune system to eliminate Drosophila cells perceived as unfit. We find that Toll-related receptors (TRRs) and the cytokine Spätzle (Spz) lead to NFκB-dependent apoptosis. Diverse “loser” cells require different TRRs and NFκB factors and activate distinct pro-death genes, implying that the particular response is stipulated by the competitive context. Our findings demonstrate a functional repurposing of components of TRRs and NFκB signaling modules in the surveillance of cell fitness during development.

Cell competition and immunity

Even in what appears to be homogeneous tissue, cell variability exists. The presence of mutant cells can compromise the functional integrity of a tissue and ultimately the organism's health. Cell competition is an internal cell surveillance mechanism that monitors cell fitness to eliminate compromised cells and prevent them from contributing to the tissue. However, how cells recognize fitness differences has remained elusive. Meyer et al. report that this recognition uses signaling pathways from the innate immune response system. Cell-cell differences in fitness activate distinct NF-κB/Rel factors in the weaker population that lead to activation of distinct pro-apoptotic genes, leading to cell death in the losing cells.

Science, this issue 10.1126/science.1258236

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