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

• Published in: Science (American Association for the Advancement of Science) Vol. 368; no. 6493; pp. 897 - 901
• Main Authors: Bálint, Š, Müller, S, Fischer, R, Kessler, B M, Harkiolaki, M, Valitutti, S, Dustin, M L
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 22-05-2020
• Subjects: CRISPR-Cas Systems; Cytotoxicity; Cytotoxicity, Immunologic; Exocytosis; Gene Editing; Granzymes - metabolism; Humans; K562 Cells; Lymphocytes; Lymphocytes T; Mass spectrometry; Multiprotein Complexes - metabolism; Perforin - metabolism; T-Lymphocytes, Cytotoxic - metabolism; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism; Tomography, X-Ray
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aay9207

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.