title: Regulatory T Cell Dysfunction Acquiesces to BTLA+ Regulatory B Cells Subsequent to Oral Intervention in Experimental Autoimmune Encephalomyelitis.
abstract: Regulatory T cells (Tregs) induced during autoimmunity often become quiescent and unable to resolve disease, suggesting inadequate activation. Resolution of established experimental autoimmune encephalomyelitis (EAE) can be achieved with myelin oligodendrocyte glycoprotein (MOG) fused to reovirus protein σ1 (MOG-pσ1), which activates Tregs, restoring protection, but requiring other regulatory cells to revitalize them. B cells have a dichotomous role in both the pathogenesis and recovery from EAE. Although inflammatory B cells contribute to EAE's pathogenesis, treatment of EAE mice with MOG-pσ1, but not OVA-pσ1, resulted in an influx of IL-10-producing B220(+)CD5(+) B regulatory cells (Bregs) enabling Tregs to recover their inhibitory activity, and in turn, leading to the rapid amelioration of EAE. These findings implicate direct interactions between Bregs and Tregs to facilitate this recovery. Adoptive transfer of B220(+)CD5(-) B cells from MOG-pσ1-treated EAE or Bregs from PBS-treated EAE mice did not resolve disease, whereas the adoptive transfer of MOG-pσ1-induced B220(+)CD5(+) Bregs greatly ameliorated EAE. MOG-pσ1-, but not OVA-pσ1-induced IL-10-producing Bregs, expressed elevated levels of B and T lymphocyte attenuator (BTLA) relative to CD5(-) B cells, as opposed to Tregs or effector T (Teff) cells, whose BTLA expression was not affected. These induced Bregs restored EAE Treg function in a BTLA-dependent manner. BTLA(-/-) mice showed more pronounced EAE with fewer Tregs, but upon adoptive transfer of MOG-pσ1-induced BTLA(+) Bregs, BTLA(-/-) mice were protected against EAE. Hence, this evidence shows the importance of BTLA in activating Tregs to facilitate recovery from EAE.
authors.affiliation: Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611; and.
authors.forename: Eduardo
authors.identifier: 0000-0001-7498-7547
authors.initials: E
authors.lastname: Huarte
authors.affiliation: Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611; and.
authors.forename: SangMu
authors.initials: S
authors.lastname: Jun
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718.
authors.forename: Agnieszka
authors.identifier: 0000-0003-4333-9971
authors.initials: A
authors.lastname: Rynda-Apple
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718.
authors.forename: Sara
authors.identifier: 0000-0002-2921-8316
authors.initials: S
authors.lastname: Golden
authors.affiliation: Department of Microbiology and Immunology, Montana State University, Bozeman, MT 59718.
authors.forename: Larissa
authors.initials: L
authors.lastname: Jackiw
authors.affiliation: Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611; and.
authors.forename: Carol
authors.initials: C
authors.lastname: Hoffman
authors.affiliation: Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611; and.
authors.forename: Massimo
authors.initials: M
authors.lastname: Maddaloni
authors.affiliation: Department of Infectious Diseases and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32611; and pascuald@ufl.edu.
authors.forename: David W
authors.identifier: 0000-0002-6572-6916
authors.initials: DW
authors.lastname: Pascual
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D018956:CD5 Antigens / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000503:physiopathology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage / Q000276:immunology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology / Q000502:physiology
chemical_list: C488868:BTLA protein, mouse; D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D011971:Receptors, Immunologic; D016753:Interleukin-10; D017493:Leukocyte Common Antigens