{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:35:50Z","timestamp":1792121750811,"version":"4.4.0"},"reference-count":32,"publisher":"American Society of Hematology","issue":"16","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,15]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Graft-versus-host disease (GVHD) remains a major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). In preclinical models, the dysregulation of interleukin-6 (IL-6) in the peritransplant period promotes GVHD via STAT3-dependent T-cell differentiation and monocyte activation, but the nature of immunological effects invoked in patients remains unclear. To advance our understanding of IL-6 signaling in humans during HSCT, we performed single-cell RNA sequencing on circulating CD14+ monocytes and CD4+ T cells from patient samples within a clinical trial of IL-6 receptor (IL-6R) inhibition (tocilizumab [TCZ] or placebo) on a backbone of calcineurin inhibition and short-course methotrexate. We studied patients who did not develop acute GVHD (aGVHD) and included a placebo-treated group analyzed before the development of aGVHD. IL-6R inhibition promoted type I interferon\u2013associated transcriptional programs in both CD4+ T cells and CD14+ monocytes. Surprisingly, IL-6R inhibition with TCZ profoundly enhanced cytolytic CD4+ T-cell differentiation. In experimental HSCT and chimeric antigen receptor T-cell systems, the genetic deletion of IL-6 signaling in donor T cells enhanced the expansion of cytolytic eomesodermin-positive (Eomes+) CD4+ regulatory T cell subsets and attenuated T helper 1 (Th1) and Th17 differentiation. Consistent with the promotion of this cytolytic CD4+ phenotype, antitumor effects were improved in the absence of IL-6 signaling. In summary, these data demonstrate that IL-6R inhibition during cell therapy imprints type I interferon programs and cytolytic CD4+ T-cell differentiation, including the Eomes+ fraction associated with favorable immunotherapy outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025032420","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T21:35:46Z","timestamp":1784756146000},"page":"2059-2071","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["IL-6 receptor inhibition promotes expansion of cytolytic CD4+ T cells after cellular immunotherapy"],"prefix":"10.1182","volume":"148","author":[{"given":"Cameron G.","family":"Williams","sequence":"first","affiliation":[{"name":"1Department of Microbiology and Immunology, Faculty of Medicine, Dentistry and Health Sciences, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, 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WA"},{"name":"4Department of Pediatrics, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashraful","family":"Haque","sequence":"additional","affiliation":[{"name":"1Department of Microbiology and Immunology, Faculty of Medicine, Dentistry and Health Sciences, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3437-9659","authenticated-orcid":false,"given":"Antiopi","family":"Varelias","sequence":"additional","affiliation":[{"name":"2QIMR Berghofer, Brisbane, Australia"},{"name":"5Faculty of Health, Medicine and Behavioural Sciences, School of Medicine, The University of Queensland, Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey R.","family":"Hill","sequence":"additional","affiliation":[{"name":"3Translational Science and Therapeutics 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