{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:22:04Z","timestamp":1787559724586,"version":"build-2736575974"},"reference-count":58,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Parasite Immunology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Visceral leishmaniasis (VL), a parasitic disease caused by\n                    <jats:italic>Leishmania donovani<\/jats:italic>\n                    , requires a robust CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cells response to control parasite replication by interferon\u2010gamma (IFN\u2010\u03b3) production and activation of macrophages. However, in VL patients, the anti\u2010parasitic CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell\u00a0responses are ineffective for reasons that are still unclear. Our recent study reporting a transcriptional signature of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell isolated from the peripheral blood of active VL patients showed enhanced expression of genes related to cytotoxicity. This study investigates the cytotoxic potential of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cells in VL patients, focusing on the expression of the key cytotoxic molecules granzyme B (GZMB), granulysin (GNLY), perforin (PRF), natural killer cell granule protein 7 (NKG7) and the degranulation capacity of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cells during infection. We observed significant upregulation of these cytotoxic markers in CD4\u207a T\u2010cells from VL patients, particularly prior to anti\u2010parasitic drug treatment (D0), suggesting activation of these cells. However, the degranulation capacity, as indicated by CD107a expression, was comparable between VL patients and endemic controls (ECs), suggesting potential functional impairment in the cytotoxic response. Yet, antigen\u2010specific GZMB secretion in whole blood cultures and intracellular GZMB production in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell\u00a0subsets (notably Th1, Th9 and Th17\/22 cells) were enhanced in VL patients, indicating a robust antigen\u2010specific response, though this did not translate into effective parasite control. These findings highlight a paradox whereby CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cells from VL patients have heightened production of cytotoxic molecules, but lack translocation of CD107a to the cell surface, which is associated with an inability to eliminate parasites. This study provides new insights into the immune dysfunction in VL, highlighting a potential role for the cytotoxic phenotype that develops in parasite\u2010specific CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cells. Targeting these pathways may offer novel therapeutic strategies to enhance immune responses and improve clinical outcomes in VL.\n                  <\/jats:p>","DOI":"10.1111\/pim.70097","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T08:08:00Z","timestamp":1787040480000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytotoxic\n                    <scp>CD4<\/scp>\n                    <sup>+<\/sup>\n                    T Cells in Visceral Leishmaniasis Patients"],"prefix":"10.1111","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3268-852X","authenticated-orcid":false,"given":"Shashi Bhushan","family":"Chauhan","sequence":"first","affiliation":[{"name":"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences Banaras Hindu University  Varanasi India"},{"name":"Department of Medicine, Institute of Medical Sciences Banaras Hindu University  Varanasi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddharth Sankar","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute of Medical Sciences Banaras Hindu University  Varanasi India"},{"name":"University of Massachusetts Chan Medical School  Worcester Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhawana","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute of Medical Sciences Banaras Hindu University  Varanasi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4126-8225","authenticated-orcid":false,"given":"Shashi","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute of Medical Sciences Banaras Hindu University  Varanasi India"},{"name":"Department of Microbiology, Tumor and Cell Biology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Tiwari","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences Banaras Hindu University  Varanasi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7956-9555","authenticated-orcid":false,"given":"Vibhav","family":"Gautam","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences Banaras Hindu University  Varanasi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Rivera","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute  Brisbane Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Nylen","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Engwerda","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Medical Research Institute  Brisbane Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyam","family":"Sundar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Institute of Medical Sciences Banaras Hindu University  Varanasi India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv","family":"Kumar","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine and Surgery, Institute of Medical Sciences Banaras Hindu University  Varanasi 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