RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8+ T cells

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Science  16 Oct 2015:
Vol. 350, Issue 6258, pp. 328-334
DOI: 10.1126/science.aad0395

Dying to impress the immune system

Besides reacting to microbes, T cells can also mount immune responses to fragments of dying cells, which they encounter displayed on dendritic cells. Not all dying cells activate T cells, however, so what differentiates the dying cells that do? Yatim et al. studied two forms of programmed cells death: apoptosis and necroptosis. Using mouse cells in culture and mouse models of inflammatory cell death and anti-tumor immunity, they found that programmed cell death initiated T cell immunity only when the dying cells signaled through the enzyme RIPK1 and the transcription factor NF-κB.

Science, this issue p. 328


Dying cells initiate adaptive immunity by providing both antigens and inflammatory stimuli for dendritic cells, which in turn activate CD8+ T cells through a process called antigen cross-priming. To define how different forms of programmed cell death influence immunity, we established models of necroptosis and apoptosis, in which dying cells are generated by receptor-interacting protein kinase-3 and caspase-8 dimerization, respectively. We found that the release of inflammatory mediators, such as damage-associated molecular patterns, by dying cells was not sufficient for CD8+ T cell cross-priming. Instead, robust cross-priming required receptor-interacting protein kinase-1 (RIPK1) signaling and nuclear factor κB (NF-κB)–induced transcription within dying cells. Decoupling NF-κB signaling from necroptosis or inflammatory apoptosis reduced priming efficiency and tumor immunity. Our results reveal that coordinated inflammatory and cell death signaling pathways within dying cells orchestrate adaptive immunity.

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