{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:06:58Z","timestamp":1771459618748,"version":"3.50.1"},"reference-count":84,"publisher":"American Society of Hematology","issue":"8","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,8,21]]},"abstract":"<jats:sec>\n                  <jats:title>Abstarct<\/jats:title>\n                  <jats:p>Developing anti\u2013factor VIII (FVIII) inhibitory antibodies (inhibitors) are a significant complication of FVIII protein replacement therapy in hemophilia A. Our previous study demonstrated that follicular helper T (TFH) cells play a critical role in FVIII inhibitor development. Follicular regulatory T (TFR) cells are a subset of forkhead box protein P3 positive (Foxp3+) T cells identified in the germinal center that can modulate TFH cell activation of B cells and antibody development. Here, we report that FVIII immunization significantly increases the TFR cells in the spleens of FVIII inhibitor-producing FVIIInull mice compared with saline-treated controls and non\u2013inhibitor-producing animals. The TFH\/TFR ratio significantly increased in FVIII inhibitor-producing mice. The emergence of TFR cells correlated with titers of FVIII inhibitors in FVIII-immunized mice. Using TFR-deficient Foxp3Cre+Bcl6fl\/fl (Bcl6FC) mice, we found that the loss of TFR cells led to significantly decreased FVIII inhibitors compared with wild-type (WT) mice on FVIII immunization (24 \u00b1 16 and 131 \u00b1 114 Bethesda unit (BU)\/mL, respectively) but not total anti-FVIII IgG levels and that TFR cells regulated IgG subclass switching and FVIII-specific B-cell responses. Interestingly, on FVIII immunization, mice with phosphatase and tensin (Pten) deficiency in Foxp3+ cells (Foxp3Cre+Ptenfl\/fl), a model with augmented TFR cells, developed markedly lower FVIII inhibitor titers (8.1 \u00b1 8.6 BU\/mL) than WT controls. When CD4Cre+Bcl6fl\/fl mice, a TFH- and TFR-deficient model, were immunized with FVIII, none of the animals developed FVIII inhibitors. In conclusion, FVIII immunization induces TFR cell activation and expansion. TFR cells have a dual function in regulating the development of FVIII inhibitors, and the TFH\/TFR pathway is pivotal in FVIII inhibitor development in mice.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2025029470","type":"journal-article","created":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T16:07:57Z","timestamp":1749571677000},"page":"998-1010","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":3,"title":["The T follicular helper\/T follicular helper regulatory pathway in FVIII immune responses in mice"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3008-9873","authenticated-orcid":false,"given":"Weiqing","family":"Jing","sequence":"first","affiliation":[{"name":"1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8953-5201","authenticated-orcid":false,"given":"Jocelyn A.","family":"Schroeder","sequence":"additional","affiliation":[{"name":"1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI"},{"name":"2Departments of Pediatrics, Cell Biology, Neurology and Anatomy, Medical College of Wisconsin, Milwaukee, WI"},{"name":"3Children\u2019s Research Institute, Children\u2019s Wisconsin, Milwaukee, WI"},{"name":"4Midwest Athletes Against Childhood Cancer Fund Research Center, Milwaukee, WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2143-6415","authenticated-orcid":false,"given":"Saurabh","family":"Kumar","sequence":"additional","affiliation":[{"name":"1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Chen","sequence":"additional","affiliation":[{"name":"1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanhua","family":"Cai","sequence":"additional","affiliation":[{"name":"1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI"},{"name":"2Departments of Pediatrics, Cell Biology, Neurology and Anatomy, Medical College of Wisconsin, Milwaukee, WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9173-7179","authenticated-orcid":false,"given":"Lynn M.","family":"Malec","sequence":"additional","affiliation":[{"name":"1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI"},{"name":"2Departments of Pediatrics, Cell Biology, Neurology and Anatomy, Medical College of Wisconsin, Milwaukee, WI"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7226-8936","authenticated-orcid":false,"given":"Alexander L.","family":"Dent","sequence":"additional","affiliation":[{"name":"5Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1562-9218","authenticated-orcid":false,"given":"Weiguo","family":"Cui","sequence":"additional","affiliation":[{"name":"1Thrombosis and Hemostasis Program, Versiti Blood Research Institute, Milwaukee, WI"},{"name":"6Department of Pathology, Northwestern University School of Medicine, Chicago, IL"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1548-0708","authenticated-orcid":false,"given":"Qizhen","family":"Shi","sequence":"additional","affiliation":[{"name":"1Thrombosis and Hemostasis Program, Versiti Blood Research 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