IL-28 supplants requirement for T(reg) cells in protein sigma1-mediated protection against murine experimental autoimmune encephalomyelitis (EAE).
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.
Rynda
Agnieszka
A
Veterinary Molecular Biology, Montana State University, Bozeman, Montana, United States of America.
Maddaloni
Massimo
M
Ochoa-Repáraz
Javier
J
Callis
Gayle
G
Pascual
David W
DW
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
D015703:Antigens, CD; D036022:Capsid Proteins; D016207:Cytokines; C511668:interferon-lambda protein, mouse; D007378:Interleukins; D000095022:Interferon Lambda; C031728:sigma 1 protein, reovirus