Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells

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Science  22 May 2020:
Vol. 368, Issue 6493, pp. 897-901
DOI: 10.1126/science.aay9207

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Supramolecular attack particles

Cytotoxic T cells (CTLs) are at the front lines against cancer and chronic infection. T cells kill by secreting caspase-activating granzymes and the pore-forming protein perforin from dense core granules. However, the structural basis of lethal hit delivery has remained unknown. Balint et al. enriched the synaptic output of CTLs to investigate the released form of perforin and granzyme B. They found that CTLs released perforin and granzymes in stable particles called supramolecular attack complexes or SMAPs. The SMAPs were composed of a core shell structure and were assembled in the CTL dense secretory granules before release. The released SMAPs showed an innate ability to kill target cells.

Science, this issue p. 897


Cytotoxic T lymphocytes (CTLs) kill infected and cancerous cells. We detected transfer of cytotoxic multiprotein complexes, called supramolecular attack particles (SMAPs), from CTLs to target cells. SMAPs were rapidly released from CTLs and were autonomously cytotoxic. Mass spectrometry, immunochemical analysis, and CRISPR editing identified a carboxyl-terminal fragment of thrombospondin-1 as an unexpected SMAP component that contributed to target killing. Direct stochastic optical reconstruction microscopy resolved a cytotoxic core surrounded by a thrombospondin-1 shell of ~120 nanometer diameter. Cryo-soft x-ray tomography analysis revealed that SMAPs had a carbon-dense shell and were stored in multicore granules. We propose that SMAPs are autonomous extracellular killing entities that deliver cytotoxic cargo targeted by the specificity of shell components.

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