Multiprotein Particles from T Cells Deliver Cytotoxic Cargo to Targets

Cytotoxic T cells can kill target cells via exocytosis of perforin 1 (PRF1), which opens pores in the plasma membranes of target cells, and granzyme B (GZMB), which enters the pores and triggers cell death pathways. It has been suggested that PRF1 and GZMB may be released in vesicles or large complexes, but the details remain murky. Balint and colleagues discovered that, upon making contact with target cells, human CD8⁺ cytotoxic T cells released multiprotein complexes, dubbed supramolecular attack particles (SMAP), that contained PRF1 and GZMB. These SMAPs were stable and capable of killing target cells even in the absence of cytotoxic T cells. Mass spectrometry revealed that SMAPs contained nearly 300 types of protein; notably, these proteins included thrombospondin-1 (TSP1), a glycoprotein that mediates cell–cell and cell–matrix interactions. Further experiments showed that SMAPs did not contain full-length TSP1, but rather contained its C-terminal Ca²⁺ binding repeats, which are thought to be responsible for TSP1-mediated cell attachment. This C-terminal TSP1 fragment localized to the surface of SMAPs, where it composed part of a dense glycoprotein-based shell of each complex. GZMB, PRF1, and serglycin, a proteoglycan that associates with GZMB and PRF1, were found inside the glycoprotein shells, which were approximately 120 nm in diameter. These and other data presented by Balint and colleagues suggest a model in which SMAPs produced by cytotoxic T cells interact with target cells via C-terminal TSP1 fragments and potentially other components of the glycoprotein shell. Once in contact with a target cell, SMAPs may then deliver their cytotoxic payload, including GZMB and PRF1, initiating destruction of the cell.

Balint Š, Müller S, Fischer R, Kessler BM, Harkiolaki M, Valitutti S, et al. Supramolecular attack particles are autonomous killing entities released from cytotoxic T cells. Science 2020;368:897–901.

Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.