{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T09:43:05Z","timestamp":1789897385421,"version":"4.0.1"},"reference-count":48,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2016,7,27]],"date-time":"2016-07-27T00:00:00Z","timestamp":1469577600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Swedish Rheumatism Association, King Gustaf V's 80-Year Foundation"},{"DOI":"10.13039\/100011103","name":"European Union Sixth Framework Programme","doi-asserted-by":"crossref","award":["LSH-018661"],"award-info":[{"award-number":["LSH-018661"]}],"id":[{"id":"10.13039\/100011103","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Stockholm County Council and Karolinska Institutet through a regional agreement on medical training and clinical research (ALF)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Inflammatory T cell infiltrates in the skeletal muscle tissue of patients with polymyositis are dominated by CD28\u2010negative effector (CD28<jats:sup>null<\/jats:sup>) T cells of both the CD4 and CD8 lineage. These cells are potentially cytotoxic, and the aim of the present study was to develop a fully autologous cell culture system in which to investigate the functional contribution of such CD28<jats:sup>null<\/jats:sup> T cells to myotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In vitro cocultures of autologous skeletal muscle cells and T cell subsets obtained from 5 polymyositis patients were performed. Myotoxicity of T cells was quantified by calcein release and flow cytometric analyses. T cell degranulation was blocked with concanamycin A. Specific blocking of perforin, cytokines, and HLA was performed using antibodies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both CD4+CD28<jats:sup>null<\/jats:sup> and CD8+CD28<jats:sup>null<\/jats:sup> T cells induced more muscle cell death than did their CD28+ counterparts. Differentiated muscle cells (myotubes) were more sensitive to T cell\u2013mediated cell death than were their precursors (myoblasts). Both CD8+ and CD4+ CD28<jats:sup>null<\/jats:sup> T cells displayed perforin polarization toward muscle cells and secreted higher levels of granzyme B and interferon\u2010\u03b3 (IFN\u03b3) in coculture than did CD28+ T cells. The myotoxic effects of CD28<jats:sup>null<\/jats:sup> T cells were reduced upon the blocking of perforin, cytokines, and HLA. Addition of IFN\u03b3 or tumor necrosis factor did not induce skeletal muscle cell death in the absence of T cells; however, it did up\u2010regulate HLA expression on muscle cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Myotoxicity of CD4+ and CD8+ CD28<jats:sup>null<\/jats:sup> T cells is mediated by directed perforin\u2010dependent killing and can be further influenced by IFN\u03b3\u2010induced HLA expression on muscle cells. The data suggest that CD28<jats:sup>null<\/jats:sup> T cells are key effector cells that contribute to the muscle cell damage in polymyositis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39650","type":"journal-article","created":{"date-parts":[[2016,2,20]],"date-time":"2016-02-20T10:48:23Z","timestamp":1455965303000},"page":"2016-2026","source":"Crossref","is-referenced-by-count":41,"title":["CD4+ and CD8+ CD28<sup>null<\/sup> T Cells Are Cytotoxic to Autologous Muscle Cells in Patients With Polymyositis"],"prefix":"10.1002","volume":"68","author":[{"given":"Jayesh M.","family":"Pandya","sequence":"first","affiliation":[{"name":"Karolinska University Hospital Solna, Sweden, and Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulius","family":"Venalis","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital Solna, Sweden, and Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lubna","family":"Al\u2010Khalili","sequence":"additional","affiliation":[{"name":"KTH Royal Institute of Technology Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Shahadat Hossain","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital Solna, Sweden, and Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Stache","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital Solna, Sweden, and Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid E.","family":"Lundberg","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital Solna, Sweden, and Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivianne","family":"Malmstr\u00f6m","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital Solna, Sweden, and Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas E. R.","family":"Fasth","sequence":"additional","affiliation":[{"name":"Andreas E. R. Fasth, PhD: Karolinska lnstitutet, Schering-Plough, MSD, and Novartis, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,7,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410160206"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410160207"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410230511"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0960-8966(94)90022-1"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118749"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27625"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803688"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.181.5.1863"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116533"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2011.39"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-92-3-365"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200002)43:2<336::AID-ANR13>3.0.CO;2-V"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2007.079525"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.11.6301"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.03.013"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(199812)41:12<2108::AID-ART5>3.0.CO;2-Q"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.0300-9475.2004.01464.x"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.10.6514"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-0974-5"},{"key":"e_1_2_8_21_1","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.4049\/jimmunol.161.2.1018","article-title":"Resistance to apoptosis and elevated expression of Bcl\u20102 in clonally expanded CD4+CD28\u2212 T cells from rheumatoid arthritis patients","volume":"161","author":"Schirmer M","year":"1998","journal-title":"J Immunol"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.013710"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.6.3725"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939399"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-014-0161-7"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197502132920706"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197502202920807"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.156.10.3678"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.100.21.2135"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00508-013-0340-4"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar2286"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410290509"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-010-0566-9"},{"key":"e_1_2_8_34_1","first-page":"1073","article-title":"The peculiar apoptotic behavior of skeletal muscle cells","volume":"28","author":"Salucci S","year":"2013","journal-title":"Histol Histopathol"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11626-013-9655-8"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4800(03)00003-0"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080422"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(96)00223-7"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2001.01499.x"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62513-8"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.10140"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27665"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.2.1138"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2567.1996.d01-689.x"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1161\/hc0502.103348"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00043.2013"},{"key":"e_1_2_8_47_1","first-page":"569","article-title":"Lytic susceptibility of target cells to cytotoxic T cells is determined by their constitutive major histocompatibility complex class I antigen expression and cytokine\u2010induced activation status","volume":"81","author":"Ritter M","year":"1994","journal-title":"Immunology"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000082333.58263.58"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12081"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.39650","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.39650","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T18:05:48Z","timestamp":1759946748000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.39650"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,27]]},"references-count":48,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,8]]}},"alternative-id":["10.1002\/art.39650"],"URL":"https:\/\/doi.org\/10.1002\/art.39650","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7,27]]}}}