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

• 成果类型: Article
• 署名作者: Cassioli, Chiara; Capitani, Nagaja; Staton, Claire C.; Schirra, Claudia; Finetti, Francesca; Onnis, Anna; Alawar, Nadia; Tu, Szu - Min; Lopresti, Ludovica; Tatangelo, Vanessa; Tangredi, Carmela; Valvo, Salvatore; Chang, Hsin - Fang; Miccoli, Annachiara; Compeer, Ewoud B.; Nicholls, Jemma; Blazar, Bruce R.; Marotta, Giuseppe; Wood, Matthew J. A.; Trentin, Livio; Patrussi, Laura; Dustin, Michael L.; Becherer, Ute; Baldari, Cosima T.
• 署名单位: University of Siena; University of Oxford; Kennedy Institute for Rheumatology; University of Oxford; Universitatsklinikum des Saarlandes; University of Minnesota System; University of Minnesota Twin Cities; University of Siena; University Hospital of Siena; University of Padua
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13854
• DOI: 10.1073/pnas.2413866122
• 发表日期: 2025-02-11
• 关键词: granule-mediated apoptosis; fas ligand; granzyme-b; cell; expression; perforin; secretion; receptor

摘要

Cytotoxic attack particles released by CTLs and NK cells include diverse phospholipid membrane and glycoprotein encapsulated entities that contribute to target cell killing. Supramolecular attack particles (SMAPs) are one type of particle characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a proteinaceous shell including thrombospondin (TSP)-1. TSP-4 was also detected in bulk analysis of SMAPs released by CTLs; however, it has not been investigated whether TSP-4 contributes to distinct SMAP types or the same SMAP type as TSP-1 and, if in the same type of SMAP, whether TSP-4 and TSP-1 cooperate or compete. Here, we observed that TSP-4 expression increased upon CD8+T cell activation while, surprisingly, TSP-1 was down- regulated. Correlative Light and Electron Microscopy and Stimulated Emission Depletion microscopy localized TSP-4 and TSP-1 in SMAP- containing multicore granules. Superresolution dSTORM revealed that TSP-4 and TSP-1 are usually enriched in the same SMAPs while particles with single- positive shells are rare. Retention Using Selective Hooks assays showed that TSP-4 localizes to the lytic granules faster than TSP-1 and promotes its accumulation therein. TSP-4 contributed to direct CTL- mediated killing, as previously shown for TSP-1. TSP-4 and TSP-1 were both required for latent SMAP- mediated cell killing, in which released SMAPs kill targets after removal of the CTLs. Of note, we found that chronic lymphocytic leukemia (CLL) cell culture supernatants suppressed expression of TSP-4 in CTL and latent SMAP- mediated killing. These results identify TSP-4 as a functionally important component of SMAPs and suggest that SMAPs may be targeted for immune suppression by CLL.