{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T19:01:15Z","timestamp":1785438075045,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,23]]},"group-title":"Immunology","reference-count":83,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/02wv5fj21","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 HL11879"],"award-info":[{"award-number":["R01 HL11879"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P01 CA065493"],"award-info":[{"award-number":["P01 CA065493"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32 HL007062"],"award-info":[{"award-number":["T32 HL007062"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"ERC Synergy","award":["951329 (ATTACK)"],"award-info":[{"award-number":["951329 (ATTACK)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Regulatory CD8\n                  <jats:sup>+<\/jats:sup>\n                  T-cells (CD8\n                  <jats:sup>+<\/jats:sup>\n                  Treg) are a distinct yet understudied T-cell subset capable of simultaneous immunosuppression and cytolysis. Here, we characterized induced human CD8\n                  <jats:sup>+<\/jats:sup>\n                  Treg (CD8-iTreg) generated from peripheral blood CD8\n                  <jats:sup>+<\/jats:sup>\n                  CD25\u207b T-cells using anti-CD3e mAb-loaded artificial antigen presenting cells, IL-2, TGF\u03b2, and Rapamycin. These CD8-iTreg differentiated into a stable, highly proliferative bifunctional population with suppressive activity comparable to CD4-iTreg while retaining cytolytic capacity similar to conventional CD8\u207a cytotoxic T lymphocytes (CTL). Multi-parameter spectral flow cytometry and single-cell RNA-seq revealed a distinct immunoregulatory signature: a predominantly Treg-like profile marked by tissue-residency marker CD103 with increased canonical Treg markers (FoxP3, HELIOS, CD25, CD39, CTLA-4, CCR4, and IL-10) and reduced pro-inflammatory cytokines. A unique cytotoxic program was marked by elevated Granzyme-K (GzmK) and Thrombospondin-4 (Tsp-4), a thrombospondin family extracellular matrix glycoprotein upregulated in activated CD8+ T-cells. Cytolysis was primarily mediated by Perforin (Prf) and multiple Granzymes packaged into Tsp-4\u207a supramolecular attack particles (SMAPs), with GzmK contributing to both cytotoxic and suppressive functions. After anti-CD19scFv CAR (CAR19) transduction, CAR19\n                  <jats:sup>+<\/jats:sup>\n                  CD8-iTreg showed superior\n                  <jats:italic>in vivo<\/jats:italic>\n                  anti-tumor efficacy compared with CAR19-CTLs, significantly reducing tumor burden and prolonging survival in a CD19\n                  <jats:sup>+<\/jats:sup>\n                  Nalm-6 human leukemia xenograft model while maintaining low pro-inflammatory cytokine production. In a xenogeneic graft-versus-host disease (GVHD) model with residual human leukemia, CAR19\u207a CD8-iTreg inhibited GVHD lethality and controlled tumor growth without increasing systemic inflammation. Together, these findings support CD8-iTreg\u2013based CAR therapies as a strategy to retain potent anti-leukemic activity while limiting inflammatory toxicities of conventional CAR T-cells, properties particularly beneficial in treating auto- and allo-immune diseases.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>\n                    CD8-iTreg drive parallel tumoricidal and immunoregulatory functions mediated by releasing Tsp-4\n                    <jats:sup>+<\/jats:sup>\n                    SMAPs containing granzyme K.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.18.731665","type":"posted-content","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T22:35:13Z","timestamp":1782254113000},"source":"Crossref","is-referenced-by-count":0,"title":["Human CD8-iTreg are potent GVHD suppressors and tumoricidal effectors by release of Granzyme-K\n                  <sup>+<\/sup>\n                  Supramolecular Attack Particles"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2920-8986","authenticated-orcid":false,"given":"Jemma H.","family":"Larson","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3050-7633","authenticated-orcid":false,"given":"Ewoud B.","family":"Compeer","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, and Chinese Academy of Medical Science-Oxford Institute, University of Oxford, OX3 7FY, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9986-1657","authenticated-orcid":false,"given":"Phillip R.","family":"Dougherty","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6971-3170","authenticated-orcid":false,"given":"Michael C.","family":"Zaiken","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1457-8973","authenticated-orcid":false,"given":"Olga","family":"Margaritaki","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, and Chinese Academy of Medical Science-Oxford Institute, University of Oxford, OX3 7FY, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Kopp","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6504-3640","authenticated-orcid":false,"given":"Sujeong","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8091-9057","authenticated-orcid":false,"given":"Maria","family":"Harkiolaki","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, and Chinese Academy of Medical Science-Oxford Institute, University of Oxford, OX3 7FY, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Chen","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, and Chinese Academy of Medical Science-Oxford Institute, University of Oxford, OX3 7FY, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Valvo","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, and Chinese Academy of Medical Science-Oxford Institute, University of Oxford, OX3 7FY, Oxford, 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9686-9802","authenticated-orcid":false,"given":"Nathaniel","family":"Payne","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6659-8194","authenticated-orcid":false,"given":"Sara","family":"Bolivar Wagers","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9576-3029","authenticated-orcid":false,"given":"Sophia","family":"Hani","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, 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