{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:34:23Z","timestamp":1792092863447,"version":"4.4.0"},"reference-count":82,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T00:00:00Z","timestamp":1657584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (DFG)","doi-asserted-by":"publisher","award":["404074532"],"award-info":[{"award-number":["404074532"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of malignant B-cells and multiple immune defects. This leads, among others, to severe infectious complications and inefficient immune surveillance. T-cell deficiencies in CLL include enhanced immune(-metabolic) exhaustion, impaired activation and cytokine production, and immunological synapse malformation. Several studies have meanwhile reported CLL-cell\u2013T-cell interactions that culminate in T-cell dysfunction. However, the complex entirety of their interplay is incompletely understood. Here, we focused on the impact of CLL cell-derived vesicles (EVs), which are known to exert immunoregulatory effects, on T-cell function. Methods: We characterized EVs secreted by CLL-cells and determined their influence on T-cells in terms of survival, activation, (metabolic) fitness, and function. Results: We found that CLL-EVs hamper T-cell viability, proliferation, activation, and metabolism while fostering their exhaustion and formation of regulatory T-cell subsets. A detailed analysis of the CLL-EV cargo revealed an abundance of immunological checkpoints (ICs) that could explain the detected T-cell dysregulations. Conclusions: The identification of a variety of ICs loaded on CLL-EVs may account for T-cell defects in CLL patients and could represent a barrier for immunotherapies such as IC blockade or adoptive T-cell transfer. Our findings could pave way for improving antitumor immunity by simultaneously targeting EV formation or multiple ICs.<\/jats:p>","DOI":"10.3390\/cells11142176","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T20:52:41Z","timestamp":1657659161000},"page":"2176","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["CLL-Derived Extracellular Vesicles Impair T-Cell Activation and Foster T-Cell Exhaustion via Multiple Immunological Checkpoints"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2911-8830","authenticated-orcid":false,"given":"Martin","family":"B\u00f6ttcher","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romy","family":"B\u00f6ttcher-Loschinski","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8813-1061","authenticated-orcid":false,"given":"Sascha","family":"Kahlfuss","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"},{"name":"Health Campus Immunology, Infectiology, and Inflammation (GCI3), Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"},{"name":"Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"},{"name":"ChaMP, Center for Health and Medical Prevention, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Aigner","sequence":"additional","affiliation":[{"name":"Medical Department 5\u2013Hematology and Oncology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9768-2049","authenticated-orcid":false,"given":"Andreas","family":"Gie\u00dfl","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Mackensen","sequence":"additional","affiliation":[{"name":"Medical Department 5\u2013Hematology and Oncology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Schl\u00f6tzer-Schrehardt","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"T\u00fcting","sequence":"additional","affiliation":[{"name":"Health Campus Immunology, Infectiology, and Inflammation (GCI3), Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"},{"name":"Laboratory for Experimental Dermatology, Department of Dermatology, Medical Faculty, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Bruns","sequence":"additional","affiliation":[{"name":"Medical Department 5\u2013Hematology and Oncology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Mougiakakos","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, University Hospital Magdeburg, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"},{"name":"Health Campus Immunology, Infectiology, and Inflammation (GCI3), Medical Center, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany"},{"name":"Medical Department 5\u2013Hematology and Oncology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-N\u00fcrnberg, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/ajh.25595","article-title":"Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment","volume":"94","author":"Hallek","year":"2019","journal-title":"Am. 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