{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:03:16Z","timestamp":1760058196390,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T00:00:00Z","timestamp":1742256000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Center in Poland","award":["2019\/35\/N\/NZ6\/02973"],"award-info":[{"award-number":["2019\/35\/N\/NZ6\/02973"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chronic lymphocytic leukaemia (CLL) is a haematological malignancy primarily affecting older adults, characterised by the proliferation of functionally impaired B lymphocytes with abnormal expression of CD5, a typical T cell marker. The current study investigates the expression of cytotoxicity-related receptors (CD16, CD56, CD57, CD69) and a checkpoint (LAG-3) on \u03b3\u03b4 T cells in CLL patients. Sixty-nine treatment-naive CLL patients and fourteen healthy controls were recruited. Flow cytometry analysis revealed that the CLL patients had higher expressions of CD56 and LAG-3 and lower CD16 on their \u03b3\u03b4 T cells compared to the healthy controls. Subgroup analysis showed that ZAP-70-negative patients exhibited increased CD69, while CD38-negative patients showed higher CD16 expression. Additionally, CD16 expression was inversely correlated with serum LDH levels, a marker of disease progression. Bioinformatic analysis of the LAG-3 ligand mRNA in a CLL dataset indicated higher expression of HLA-DQA2 and HLA-DRB5 in patients with unmutated IGVH. Our findings highlight the altered expression of key cytotoxicity markers on \u03b3\u03b4 T cells in CLL, suggesting their potential role in disease progression and as a therapeutic target. In particular, the use of anti-LAG-3 antibodies seems promising.<\/jats:p>","DOI":"10.3390\/cells14060451","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T04:34:43Z","timestamp":1742272483000},"page":"451","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterisation of Cytotoxicity-Related Receptors on \u03b3\u03b4 T Cells in Chronic Lymphocytic Leukaemia"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-6353","authenticated-orcid":false,"given":"Micha\u0142","family":"Zarobkiewicz","sequence":"first","affiliation":[{"name":"Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2324-5679","authenticated-orcid":false,"given":"Natalia","family":"Lehman","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Izabela","family":"Morawska-Michalska","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9598-373X","authenticated-orcid":false,"given":"Adam","family":"Michalski","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0930-5874","authenticated-orcid":false,"given":"Wioleta","family":"Kowalska","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3764-7452","authenticated-orcid":false,"given":"Agata","family":"Szyma\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3205-5781","authenticated-orcid":false,"given":"Waldemar","family":"Tomczak","sequence":"additional","affiliation":[{"name":"Department of Haematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-080 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2340-9442","authenticated-orcid":false,"given":"Agnieszka","family":"Bojarska-Junak","sequence":"additional","affiliation":[{"name":"Department of Clinical Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,18]]},"reference":[{"doi-asserted-by":"crossref","unstructured":"Yee, K.W.L., Keating, M.J., and O\u2019Brien, S.M. (2008). Treatment of Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Chronic Lymphocytic Leukemia, CRC Press.","key":"ref_1","DOI":"10.3109\/9781420068962-11"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1007\/s40266-019-00678-5","article-title":"Treating Older Patients with Chronic Lymphocytic Leukemia: A Personalized Approach","volume":"36","author":"Strati","year":"2019","journal-title":"Drugs Aging"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/j.1365-2567.2012.03582.x","article-title":"Understanding the Complexity of \u0393\u03b4 T-Cell Subsets in Mouse and Human","volume":"136","author":"Pang","year":"2012","journal-title":"Immunology"},{"doi-asserted-by":"crossref","unstructured":"Clark, B.L., and Thomas, P.G. (2020). A Cell for the Ages: Human \u0393\u03b4 t Cells across the Lifespan. Int. J. Mol. Sci., 21.","key":"ref_4","DOI":"10.3390\/ijms21238903"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.exger.2004.07.005","article-title":"Impairment of Gamma\/Delta T Lymphocytes in Elderly: Implications for Immunosenescence","volume":"39","author":"Aquino","year":"2004","journal-title":"Exp. Gerontol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nri3384","article-title":"Six-of-the-Best: Unique Contributions of \u0393\u03b4 T Cells to Immunology","volume":"13","author":"Vantourout","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/imr.12930","article-title":"Diversity in Recognition and Function of Human \u0393\u03b4 T Cells","volume":"298","author":"Castro","year":"2020","journal-title":"Immunol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/imr.12923","article-title":"Immune Recognition of Phosphoantigen-Butyrophilin Molecular Complexes by \u0393\u03b4 T Cells","volume":"298","author":"Uldrich","year":"2020","journal-title":"Immunol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4232","DOI":"10.1158\/1078-0432.CCR-07-4912","article-title":"Isopentenyl Pyrophosphate-Activated CD56+ \u0393\u03b4 T Lymphocytes Display Potent Antitumor Activity toward Human Squamous Cell Carcinoma","volume":"14","author":"Alexander","year":"2008","journal-title":"Clin. Cancer Res."},{"doi-asserted-by":"crossref","unstructured":"N\u00f6renberg, J., Jaks\u00f3, P., and Barakonyi, A. (2021). Gamma\/Delta T Cells in the Course of Healthy Human Pregnancy: Cytotoxic Potential and the Tendency of CD8 Expression Make CD56+ \u03b3\u03b4T Cells a Unique Lymphocyte Subset. Front. Immunol., 11.","key":"ref_10","DOI":"10.3389\/fimmu.2020.596489"},{"doi-asserted-by":"crossref","unstructured":"Siegers, G.M., Felizardo, T.C., Mark Mathieson, A., Kosaka, Y., Wang, X.-H., Medin, J.A., and Keating, A. (2011). Anti-Leukemia Activity of in Vitro-Expanded Human Gamma Delta T Cells in a Xenogeneic Ph+ Leukemia Model. PLoS ONE, 6.","key":"ref_11","DOI":"10.1371\/journal.pone.0016700"},{"doi-asserted-by":"crossref","unstructured":"Tuengel, J., Ranchal, S., Maslova, A., Aulakh, G., Papadopoulou, M., Drissler, S., Cai, B., Mohsenzadeh-Green, C., Soudeyns, H., and Mostafavi, S. (2021). Characterization of Adaptive-like \u0393\u03b4 t Cells in Ugandan Infants during Primary Cytomegalovirus Infection. Viruses, 13.","key":"ref_12","DOI":"10.3390\/v13101987"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12943-023-01722-0","article-title":"Gamma Delta T-Cell-Based Immune Checkpoint Therapy: Attractive Candidate for Antitumor Treatment","volume":"22","author":"Gao","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1182\/blood.V46.2.219.219","article-title":"Clinical Staging of Chronic Lymphocytic Leukemia","volume":"46","author":"Rai","year":"1975","journal-title":"Blood"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"43","DOI":"10.17219\/acem\/186335","article-title":"Expression of CD226 on \u0393\u03b4 T Cells Is Lower in Advanced Chronic Lymphocytic Leukemia and Correlates with IgA, IgG and LDH Levels","volume":"34","author":"Zarobkiewicz","year":"2024","journal-title":"Adv. Clin. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nature15395","article-title":"Mutations Driving CLL and Their Evolution in Progression and Relapse","volume":"526","author":"Landau","year":"2015","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal."},{"doi-asserted-by":"crossref","unstructured":"Zarobkiewicz, M., Kowalska, W., Chocholska, S., Tomczak, W., Szyma\u0144ska, A., Morawska, I., Wojciechowska, A., and Bojarska-Junak, A. (2020). High M-MDSC Percentage as a Negative Prognostic Factor in Chronic Lymphocytic Leukaemia. Cancers, 12.","key":"ref_19","DOI":"10.3390\/cancers12092614"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1111\/cas.16401","article-title":"Elotuzumab-Mediated ADCC with Th1-like V\u03b39V\u03b42 T Cells to Disrupt Myeloma\u2013Osteoclast Interaction","volume":"116","author":"Inoue","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"101962","DOI":"10.1016\/j.trim.2023.101962","article-title":"Examining the Impact of Immunosuppressive Drugs on Antibody-Dependent Cellular Cytotoxicity (ADCC) of Human Peripheral Blood Natural Killer (NK) Cells and Gamma Delta (\u0393\u03b4) T Cells","volume":"82","author":"Jalali","year":"2024","journal-title":"Transpl. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"383","DOI":"10.3923\/ijcr.2006.383.389","article-title":"Role of Serum Lactate Dehydrogenase as a Bio-Marker in Therapy Related Hematological Malignancies","volume":"2","author":"Mani","year":"2006","journal-title":"Int. J. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1002\/ajh.21756","article-title":"Low CD49d Expression and Long Telomere Identify a Chronic Lymphocytic Leukemia Subset with Highly Favourable Outcome","volume":"85","author":"Rossi","year":"2010","journal-title":"Am. J. Hematol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.jneuroim.2007.11.010","article-title":"Correlation of Specialized CD16(+) Gammadelta T Cells with Disease Course and Severity in Multiple Sclerosis","volume":"194","author":"Chen","year":"2008","journal-title":"J. Neuroimmunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3370","DOI":"10.1002\/eji.200425587","article-title":"Down-Regulation of CXCR4 Expression on Human CD8+ T Cells during Peripheral Differentation","volume":"34","author":"Kobayashi","year":"2004","journal-title":"Eur. J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5720","DOI":"10.1158\/1078-0432.CCR-13-3464","article-title":"Neuroblastoma Killing Properties of V\u03b42 and V\u03b42-Negative \u03b3\u03b4T Cells Following Expansion by Artificial Antigen-Presenting Cells","volume":"20","author":"Fisher","year":"2014","journal-title":"Clin. Cancer Res."},{"doi-asserted-by":"crossref","unstructured":"Catafal-Tardos, E., Baglioni, M.V., and Bekiaris, V. (2021). Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in \u0393\u03b4 T, MAIT, and NKT Cells. Cancers, 13.","key":"ref_27","DOI":"10.3390\/cancers13184647"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1601483","DOI":"10.1080\/2162402X.2019.1601483","article-title":"The Features of Circulating and Tumor-Infiltrating \u0393\u03b4 T Cells in Melanoma Patients Display Critical Perturbations with Prognostic Impact on Clinical Outcome","volume":"8","author":"Girard","year":"2019","journal-title":"OncoImmunology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1111\/j.1365-2362.2011.02524.x","article-title":"Impaired Function of Gamma\u2013Delta Lymphocytes in Melanoma Patients","volume":"41","author":"Petrini","year":"2011","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1093\/jleuko\/qiae023","article-title":"Tumor-Infiltrating \u0393\u03b4 T Cells as Targets of Immune Checkpoint Blockade in Melanoma","volume":"115","author":"Simone","year":"2024","journal-title":"J. Leukoc. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e12594","DOI":"10.1111\/pim.12594","article-title":"Exposure to Plasmodium Vivax Is Associated with the Increased Expression of Exhaustion Markers on \u0393\u03b4 T Lymphocytes","volume":"40","author":"Gogoi","year":"2018","journal-title":"Parasite Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1007\/s00262-022-03164-x","article-title":"Transient 40 \u00b0C-Shock Potentiates Cytotoxic Responses of V\u03b42+ \u0393\u03b4 T Cell via HSP70 Upregulation","volume":"71","author":"Lin","year":"2022","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"874","DOI":"10.3324\/haematol.2016.148965","article-title":"Lymphocyte Activation Gene 3: A Novel Therapeutic Target in Chronic Lymphocytic Leukemia","volume":"102","author":"Shapiro","year":"2017","journal-title":"Haematologica"},{"key":"ref_34","first-page":"809","article-title":"Assessment of LAG3 and Galnt11 Gene Expression in Patients With Chronic Lymphocytic Leukemia and Their Impact on Disease Progression","volume":"21","author":"Alobaidi","year":"2021","journal-title":"Biochem. Cell. Arch."},{"doi-asserted-by":"crossref","unstructured":"Sordo-bahamonde, C., Lorenzo-herrero, S., Gonz\u00e1lez-rodr\u00edguez, A.P., Payer, \u00c1.R., Gonz\u00e1lez-garc\u00eda, E., L\u00f3pez-soto, A., and Gonzalez, S. (2021). Lag-3 Blockade with Relatlimab (Bms-986016) Restores Anti-leukemic Responses in Chronic Lymphocytic Leukemia. Cancers, 13.","key":"ref_35","DOI":"10.3390\/cancers13092112"},{"doi-asserted-by":"crossref","unstructured":"Wo\u015b, J., Szyma\u0144ska, A., Lehman, N., Chocholska, S., Zarobkiewicz, M., Po\u017carowski, P., and Bojarska-Junak, A. (2024). Can Galectin-3 Be a Novel Biomarker in Chronic Lymphocytic Leukemia?. Cells, 13.","key":"ref_36","DOI":"10.3390\/cells13010030"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1002\/eji.201646837","article-title":"CD69: From Activation Marker to Metabolic Gatekeeper","volume":"47","year":"2017","journal-title":"Eur. J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.molimm.2024.06.006","article-title":"CD69+ V\u03b41\u03b3\u03b4 T Cells Are Anti-Tumor Subpopulations in Hepatocellular Carcinoma","volume":"172","author":"You","year":"2024","journal-title":"Mol. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/1479-5876-12-187","article-title":"Non-Traditional CD4+CD25-CD69+ Regulatory T Cells Are Correlated to Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation","volume":"12","author":"Zhao","year":"2014","journal-title":"J. Transl. Med."},{"doi-asserted-by":"crossref","unstructured":"Kouakanou, L., Peters, C., Sun, Q., Floess, S., Bhat, J., Huehn, J., and Kabelitz, D. (2020). Vitamin C Supports Conversion of Human \u0393\u03b4 T Cells into FOXP3-Expressing Regulatory Cells by Epigenetic Regulation. Sci. Rep., 10.","key":"ref_40","DOI":"10.1038\/s41598-020-63572-w"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1748991","DOI":"10.1080\/2162402X.2020.1748991","article-title":"B7-H3 Inhibits the IFN-\u03b3-Dependent Cytotoxicity of V\u03b39V\u03b42 T Cells against Colon Cancer Cells","volume":"9","author":"Lu","year":"2020","journal-title":"OncoImmunology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"753","DOI":"10.3109\/14653249.2011.553595","article-title":"Human V\u03b41 \u0393\u03b4 T Cells Expanded from Peripheral Blood Exhibit Specific Cytotoxicity against B-Cell Chronic Lymphocytic Leukemia-Derived Cells","volume":"13","author":"Siegers","year":"2011","journal-title":"Cytotherapy"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/00002371-200501000-00009","article-title":"Human \u0393\u03b4 T Cells from G-CSF-Mobilized Donors Retain Strong Tumoricidal Activity and Produce Immunomodulatory Cytokines after Clinical-Scale Isolation","volume":"28","author":"Otto","year":"2005","journal-title":"J. Immunother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"11861","DOI":"10.1128\/JVI.02013-14","article-title":"High Eomesodermin Expression among CD57+ CD8+ T Cells Identifies a CD8+ T Cell Subset Associated with Viral Control during Chronic Human Immunodeficiency Virus Infection","volume":"88","author":"Simonetta","year":"2014","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00262-016-1803-z","article-title":"CD57 in Human Natural Killer Cells and T-Lymphocytes","volume":"65","author":"Kared","year":"2016","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5145","DOI":"10.4049\/jimmunol.177.8.5145","article-title":"High Cytotoxic and Specific Migratory Potencies of Senescent CD8+CD57+ Cells in HIV-Infected and Uninfected Individuals1","volume":"177","author":"Puthier","year":"2006","journal-title":"J. Immunol."},{"key":"ref_47","first-page":"1482","article-title":"Clonal Expansion within the CD4+CD57+ and CD8+CD57+ T Cell Subsets in Chronic Lymphocytic Leukemia","volume":"158","author":"Serrano","year":"1997","journal-title":"J. Immunol. Baltim. Md 1950"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1002\/path.1894","article-title":"Cytokine Gene Expression Profile Distinguishes CD4+\/CD57+ T Cells of the Nodular Lymphocyte Predominance Type of Hodgkin\u2019s Lymphoma from Their Tonsillar Counterparts","volume":"208","author":"Atayar","year":"2006","journal-title":"J. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0145-2126(97)00152-5","article-title":"Peripheral Blood Lymphocyte Subset Shifts in Patients with Untreated Hematological Tumors: Evidence for Systemic Activation of the T Cell Compartment","volume":"22","author":"Vandenberghe","year":"1998","journal-title":"Leuk. Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/6\/451\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:55:38Z","timestamp":1760028938000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/6\/451"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,18]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["cells14060451"],"URL":"https:\/\/doi.org\/10.3390\/cells14060451","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2025,3,18]]}}}