title: IL-28 supplants requirement for T(reg) cells in protein sigma1-mediated protection against murine experimental autoimmune encephalomyelitis (EAE).
abstract: Conventional methods to induce tolerance in humans have met with limited success. Hence, efforts to redirect tolerogen uptake using reovirus adhesin, protein sigma 1 (psigma1), may circumvent these shortcomings based upon the recent finding that when reovirus psigma1 is engineered to deliver chicken ovalbumin (OVA) mucosally, tolerance is obtained, even with a single dose. To test whether single-dose tolerance can be induced to treat EAE, proteolipid protein (PLP(130-151)) was genetically fused to OVA to psigma1 (PLP:OVA-psigma1) and shown to significantly ameliorate EAE, suppressing proinflammatory cytokines by IL-10(+) forkhead box P3 (FoxP3)(+) CD25(+)CD4(+) T(reg) and IL-4(+)CD25(-)CD4(+) Th2 cells. IL-10R or IL-4 neutralization reversed protection to EAE conferred by PLP:OVA-psigma1, and adoptive transfer of Ag-specific T(reg) or Th2 cells restored protection against EAE in recipients. Upon assessment of each relative participant, functional inactivation of CD25 impaired PLP:OVA-psigma1's protective capacity, triggering TGF-beta-mediated inflammation; however, concomitant inactivation of TGF-beta and CD25 reestablished PLP:OVA-psigma1-mediated protection by IL-28-producing FoxP3(+)CD25(-)CD4(+) T cells. Thus, psigma1-based therapy can resolve EAE independently of or dependently upon CD25 and assigns IL-28 as an alternative therapy for autoimmunity.
authors.affiliation: Veterinary Molecular Biology, Montana State University, Bozeman, Montana, United States of America.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Rynda
authors.forename: Massimo
authors.initials: M
authors.lastname: Maddaloni
authors.forename: Javier
authors.initials: J
authors.lastname: Ochoa-Repáraz
authors.forename: Gayle
authors.initials: G
authors.lastname: Callis
authors.forename: David W
authors.initials: DW
authors.lastname: Pascual
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D036022:Capsid Proteins / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000517:prevention & control*; D005260:Female; D051379:Mice; D009500:Neutralization Tests; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D007378:Interleukins; D000095022:Interferon Lambda
chemical_list: D015703:Antigens, CD; D036022:Capsid Proteins; D016207:Cytokines; C511668:interferon-lambda protein, mouse; D007378:Interleukins; D000095022:Interferon Lambda; C031728:sigma 1 protein, reovirus