title: Lymphocyte-activation gene 3(+) (LAG3(+)) forkhead box protein 3(-) (FOXP3(-)) regulatory T cells induced by B cells alleviates joint inflammation in collagen-induced arthritis.
abstract: Rheumatoid arthritis (RA) is an autoimmune disease in which dysregulated immune cells primarily target synovial joints. Despite recent advances in the treatment of RA, including the introduction of biologic therapies and employment of combination disease-modifying antirheumatic drug strategies, remission rates remain suboptimal. Previous studies have demonstrated that the adoptive transfer of induced regulatory T cells (iTregs) was effective in treating a murine model of collagen-induced arthritis (CIA). The objective of this study was to develop optimal potential iTreg-based therapy for CIA by adoptively transferring LAG3(+) Treg-of-B cells. B-cell-induced Treg-of-B cells expressed LAG3 but not Foxp3 (designated LAG3(+) Treg-of-B), and secreted IL-4, IL-10, and TGF-β. Furthermore, LAG3(+) Treg-of-B cells suppressed the proliferation of CD4(+)CD25(-) responder T cells through both LAG3 and IL-10 production. In the murine CIA model, adoptive transfer of LAG3(+) Treg-of-B cells alleviated the joint severity as well as local and systemic inflammation. Treatment with LAG3(+) Treg-of-B cells also promoted IL-10 production in lymphocytes isolated from the spleen and draining lymph nodes. Moreover, mice receiving LAG3(+) Treg-of-B cell treatment showed significantly less pronounced osteolysis in the hind footpads, which correlated with the downregulation of tartrate-resistant acid phosphatase expression. In conclusion, we identified a novel subset of Tregs for CIA treatment. This insight may facilitate exploring novel regulatory T-cell-based therapies for human autoimmune diseases.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Szu-Ying
authors.initials: SY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Wan-Tseng
authors.initials: WT
authors.lastname: Hsu
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Lien
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chien-Hui
authors.initials: CH
authors.lastname: Chien
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: gicmbor@ntu.edu.tw.
authors.forename: Bor-Luen
authors.initials: BL
authors.lastname: Chiang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002450:Cell Communication / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D056747:Immunomodulation; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018836:Inflammation Mediators; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse
keywords: Collagen-induced arthritis; Lymphocyte-activation gene 3; Regulatory T cells; Rheumatoid arthritis