{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:06:45Z","timestamp":1792649205113,"version":"4.5.0"},"reference-count":50,"publisher":"National Academy of Sciences","issue":"6","license":[{"start":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:00:00Z","timestamp":1738627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["951329"],"award-info":[{"award-number":["951329"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["2R01HL118979"],"award-info":[{"award-number":["2R01HL118979"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["IG 2017-20148"],"award-info":[{"award-number":["IG 2017-20148"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014748","name":"\u725b\u6d25\u5927\u5b66 | Clarendon Fund","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100014748","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005690","name":"Universit\u00e4t des Saarlandes","doi-asserted-by":"publisher","award":["HOMFORexzellent2020"],"award-info":[{"award-number":["HOMFORexzellent2020"]}],"id":[{"id":"10.13039\/501100005690","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016580","name":"Kennedy Trust for Rheumatology Research","doi-asserted-by":"publisher","award":["Cell Dynamics Platform"],"award-info":[{"award-number":["Cell Dynamics Platform"]}],"id":[{"id":"10.13039\/100016580","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,2,11]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2413866122","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T10:11:06Z","timestamp":1738663866000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":11,"title":["Activation-induced thrombospondin-4 works with thrombospondin-1 to build cytotoxic supramolecular attack particles"],"prefix":"10.1073","volume":"122","author":[{"given":"Chiara","family":"Cassioli","sequence":"first","affiliation":[{"name":"Department of Life Sciences, University of Siena","place":["Siena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagaja","family":"Capitani","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena","place":["Siena, 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Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Tatangelo","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena","place":["Siena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Tangredi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena","place":["Siena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Valvo","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Fang","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, Saarland 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Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota","place":["Minneapolis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Marotta","sequence":"additional","affiliation":[{"name":"Stem Cell Transplant and Cellular Therapy Unit, Siena University Hospital","place":["Siena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J. A.","family":"Wood","sequence":"additional","affiliation":[{"name":"Institute for Developmental and Regenerative Medicine, Department of Paediatrics, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livio","family":"Trentin","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Medicine, University of Padua","place":["Padua, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Patrussi","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena","place":["Siena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4983-6389","authenticated-orcid":false,"given":"Michael L.","family":"Dustin","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of 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lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug","volume":"118","author":"Ramsay A. G.","year":"2008","unstructured":"A. G. Ramsay , Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J. Clin. Invest. 118, 2427\u20132437 (2008).","journal-title":"J. Clin. Invest."},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2015.11.003"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21051825"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-3135-5_27"},{"key":"e_1_3_4_50_2","unstructured":"M. L. Dustin Activation induced Thrombospondin-4 works with Thrombospondin-1 to build cytotoxic supramolecular attack particles. OSF. https:\/\/osf.io\/4gzsm\/. Deposited 20 January 2025."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2413866122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T10:11:32Z","timestamp":1738663892000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2413866122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,4]]},"references-count":50,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,2,11]]}},"alternative-id":["10.1073\/pnas.2413866122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2413866122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,4]]},"assertion":[{"value":"2024-07-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2413866122"}}