{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:55:10Z","timestamp":1792086910758,"version":"4.4.0"},"reference-count":25,"publisher":"American Society of Hematology","issue":"21","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,11,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A unique feature of Hodgkin lymphoma (HL) is the presence of CD4+ T cells that surround, protect, and promote survival of tumor cells. The adhesion molecules involved in this so-called T-cell rosetting are important components of the immunological synapse (IS). However, it is unknown whether this synapse is fully assembled and leads to T-cell activation by enabling interaction between the T-cell receptor (TCR) and human leukocyte antigen class II (HLA-II). We established a novel rosetting model by coculturing HLA-II\u2013matched peripheral blood mononuclear cells with HL cell lines and showed IS formation with activation of rosetting T cells. HLA-II downregulation by class II transactivator knockout did not affect the extent of rosetting, but almost completely abrogated T-cell activation. Intriguingly, the level of CD58 expression correlated with the extent of rosette formation, and CD58 knockout or CD2 blockade reduced both rosette formation and T-cell activation. The extension of our findings to primary HL tissue by immunohistochemistry and proximity ligation assays showed interaction of CD2 with CD58 and of TCR-associated CD4 with HLA-II. In conclusion, T-cell rosetting in HL is established by formation of the IS, and activation of rosetting T cells critically depends on the interaction of both TCR-HLA-II and CD2-CD58.<\/jats:p>","DOI":"10.1182\/blood.2020005546","type":"journal-article","created":{"date-parts":[[2020,6,27]],"date-time":"2020-06-27T03:36:16Z","timestamp":1593228976000},"page":"2437-2441","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":49,"title":["Rosetting T cells in Hodgkin lymphoma are activated by immunological synapse components HLA class II and CD58"],"prefix":"10.1182","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4253-0870","authenticated-orcid":false,"given":"Johanna","family":"Veldman","sequence":"first","affiliation":[{"name":"Department of Pathology and Medical Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Visser","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Huberts-Kregel","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasja","family":"Muller","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bouke","family":"Hepkema","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9239-1050","authenticated-orcid":false,"given":"Arjan","family":"Diepstra","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"2","key":"2020111911322174800_B1","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1182\/blood.V59.2.226.226","article-title":"In situ immunologic characterization of cellular constituents in lymph nodes and spleens involved by Hodgkin\u2019s disease","volume":"59","author":"Poppema","year":"1982","journal-title":"Blood"},{"issue":"2","key":"2020111911322174800_B2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/path.1711220205","article-title":"Rosetting and other reactions of the Reed-Sternberg cell","volume":"122","author":"Stuart","year":"1977","journal-title":"J Pathol"},{"key":"2020111911322174800_B3","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.semcancer.2013.07.002","article-title":"The microenvironment in classical Hodgkin lymphoma: an actively shaped and essential tumor component","volume":"24","author":"Liu","year":"2014","journal-title":"Semin Cancer Biol"},{"key":"2020111911322174800_B4","doi-asserted-by":"crossref","first-page":"101931","DOI":"10.1016\/j.ctrv.2019.101931","article-title":"Primary and acquired resistance mechanisms to immune checkpoint inhibition in Hodgkin lymphoma","volume":"82","author":"Veldman","year":"2020","journal-title":"Cancer Treat Rev"},{"issue":"5","key":"2020111911322174800_B5","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1309\/7371XK6F6P7474XX","article-title":"Identification and purification of classical Hodgkin cells from lymph nodes by flow cytometry and flow cytometric cell sorting","volume":"126","author":"Fromm","year":"2006","journal-title":"Am J Clin Pathol"},{"issue":"1","key":"2020111911322174800_B6","first-page":"37","article-title":"Molecular pathways of adhesion in spontaneous rosetting of T-lymphocytes to the Hodgkin\u2019s cell line L428","volume":"48","author":"Sanders","year":"1988","journal-title":"Cancer Res"},{"issue":"6","key":"2020111911322174800_B7","doi-asserted-by":"crossref","first-page":"e1160186","DOI":"10.1080\/2162402X.2016.1160186","article-title":"Tumor-infiltrating HLA-matched CD4(+) T cells retargeted against Hodgkin and Reed-Sternberg cells","volume":"5","author":"Rengstl","year":"2016","journal-title":"OncoImmunology"},{"issue":"5425","key":"2020111911322174800_B8","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1126\/science.285.5425.221","article-title":"The immunological synapse: a molecular machine controlling T cell activation","volume":"285","author":"Grakoui","year":"1999","journal-title":"Science"},{"issue":"51","key":"2020111911322174800_B9","doi-asserted-by":"crossref","first-page":"20296","DOI":"10.1073\/pnas.0710258105","article-title":"Mechanisms for segregating T cell receptor and adhesion molecules during immunological synapse formation in Jurkat T cells","volume":"104","author":"Kaizuka","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"issue":"9","key":"2020111911322174800_B10","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.4049\/jimmunol.168.9.4287","article-title":"Cutting edge: TCR engagement and triggering in the absence of large-scale molecular segregation at the T cell-APC contact site","volume":"168","author":"Zaru","year":"2002","journal-title":"J Immunol"},{"issue":"2","key":"2020111911322174800_B11","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/bjc.1989.35","article-title":"The Reed-Sternberg cell\/lymphocyte rosette. I. Properties of rosettes formed between Hodgkin\u2019s cell lines and allogeneic lymphocytes","volume":"59","author":"Flavell","year":"1989","journal-title":"Br J Cancer"},{"issue":"6","key":"2020111911322174800_B12","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/gene.2016.30","article-title":"CD58 mutations are common in Hodgkin lymphoma cell lines and loss of CD58 expression in tumor cells occurs in Hodgkin lymphoma patients who relapse","volume":"17","author":"Abdul Razak","year":"2016","journal-title":"Genes Immun"},{"issue":"21","key":"2020111911322174800_B13","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1200\/JCO.2006.10.0917","article-title":"HLA class II expression by Hodgkin Reed-Sternberg cells is an independent prognostic factor in classical Hodgkin\u2019s lymphoma","volume":"25","author":"Diepstra","year":"2007","journal-title":"J Clin Oncol"},{"issue":"10","key":"2020111911322174800_B14","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1002\/gcc.22276","article-title":"Alterations of the CD58 gene in classical Hodgkin lymphoma","volume":"54","author":"Schneider","year":"2015","journal-title":"Genes Chromosomes Cancer"},{"issue":"5","key":"2020111911322174800_B15","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0960-9822(00)00362-6","article-title":"Exclusion of CD45 from the T-cell receptor signaling area in antigen-stimulated T lymphocytes","volume":"10","author":"Leupin","year":"2000","journal-title":"Curr Biol"},{"issue":"10","key":"2020111911322174800_B16","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1084\/jem.190.10.1383","article-title":"CD2 sets quantitative thresholds in T cell activation","volume":"190","author":"Bachmann","year":"1999","journal-title":"J Exp Med"},{"issue":"5","key":"2020111911322174800_B17","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/S0092-8674(00)81608-6","article-title":"A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts","volume":"94","author":"Dustin","year":"1998","journal-title":"Cell"},{"issue":"3","key":"2020111911322174800_B18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1093\/intimm\/dxl141","article-title":"CD2 and TCR synergize for the activation of phospholipase Cgamma1\/calcium pathway at the immunological synapse","volume":"19","author":"Espagnolle","year":"2007","journal-title":"Int Immunol"},{"key":"2020111911322174800_B19","doi-asserted-by":"crossref","unstructured":"Demetriou\n              P\n            , Abu-ShahE, McCuaigS, et al\n          CD2 expression acts as a quantitative checkpoint for immunological synapse structure and T-cell activation [published online ahead of print 29 March 2019].\n          bioRxiv. doi:10.1101\/589440.","DOI":"10.1101\/589440"},{"issue":"11","key":"2020111911322174800_B20","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1038\/leu.2014.201","article-title":"The mutational landscape of Hodgkin lymphoma cell lines determined by whole-exome sequencing","volume":"28","author":"Liu","year":"2014","journal-title":"Leukemia"},{"issue":"2","key":"2020111911322174800_B21","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1634\/theoncologist.2018-0058","article-title":"Comprehensive genomic profiling of hodgkin lymphoma reveals recurrently mutated genes and increased mutation burden","volume":"24","author":"Liang","year":"2019","journal-title":"Oncologist"},{"issue":"8","key":"2020111911322174800_B22","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1002\/(SICI)1521-4141(199808)28:08<2424::AID-IMMU2424>3.0.CO;2-R","article-title":"Amplification of TCRbeta gene rearrangements from micromanipulated single cells: T cells rosetting around Hodgkin and Reed-Sternberg cells in Hodgkin\u2019s disease are polyclonal","volume":"28","author":"Roers","year":"1998","journal-title":"Eur J Immunol"},{"issue":"17","key":"2020111911322174800_B23","doi-asserted-by":"crossref","first-page":"3268","DOI":"10.1182\/blood-2010-05-282780","article-title":"Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma","volume":"116","author":"Green","year":"2010","journal-title":"Blood"},{"issue":"8","key":"2020111911322174800_B24","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1182\/blood-2018-04-843714","article-title":"Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell-rich and exhausted T-effector microenvironment","volume":"132","author":"Cader","year":"2018","journal-title":"Blood"},{"issue":"5","key":"2020111911322174800_B25","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1182\/blood-2003-07-2594","article-title":"Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma","volume":"103","author":"Marshall","year":"2004","journal-title":"Blood"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/136\/21\/2437\/1789987\/bloodbld2020005546.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/136\/21\/2437\/1789987\/bloodbld2020005546.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T14:33:16Z","timestamp":1605796396000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/136\/21\/2437\/461197\/Rosetting-T-cells-in-Hodgkin-lymphoma-are"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,19]]},"references-count":25,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2020,11,19]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2020005546","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,19]]}}}