2025
PNAS

Activation-induced thrombospondin-4 works with thrombospondin-1 to build cytotoxic supramolecular attack particles

Authors:

Chiara Cassiolia, Nagaja Capitania, Claire C. Statonb,c,1, Claudia Schirrad,1, Francesca Finettia, Anna Onnisa, Nadia Alaward, Szu-Min Tud, Ludovica Loprestia, Vanessa Tatangeloa, Carmela Tangredia, Salvatore Valvob, Hsin-Fang Changd, Annachiara Miccolia, Ewoud B. Compeerb, Jemma Nichollse, Bruce R. Blazare, Giuseppe Marottaf, Matthew J. A. Woodc, Livio Trenting, Laura Patrussia, Michael L. Dustin, Ute Becherer, Cosima T. Baldari

Keywords:

Cytotoxic T cells; CTLs; thrombospondin; TSP-1; TSP-4; supramolecular attack particles; SMAPs

Abstract:

Cytotoxic T cells (CTLs) kill infected and cancer cells by introduction of granzymes into the cytoplasm of the target in a perforin-dependent manner. We have recently demonstrated that thrombospondin-1 (TSP-1) plays an important role in this process through encapsulating half of the released granzymes and perforin in supramolecular attack particles (SMAPs). Surprisingly, TSP-1 mRNA was down-regulated on T cell activation. In contrast, TSP-4 mRNA, which was not studied previously, was up-regulated. We demonstrate that TSP-1 and TSP-4 coassembled into the SMAPs and that they are both required for full CTL- and SMAP-mediated cytotoxicity. TSP-4 reaches granules in CTL faster than TSP-1. Chronic lymphocytic leukemia cells produce factors that impair expression of TSP-4, suggesting an immune evasion strategy.