IL-28 supplants requirement for T_reg cells in protein σ1-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 (pσ1), may circumvent these shortcomings based upon the recent finding that when reovirus pσ1 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 pσ1 (PLP:OVA-pσ1) and shown to significantly ameliorate EAE, suppressing proinflammatory cytokines by IL-10⁺ forkhead box P3 (FoxP3) ⁺ CD25⁺CD4⁺ T_reg and IL-4+CD252CD4+ Th2 cells. IL-10R or IL-4 neutralization reversed protection to EAE conferred by PLP:OVA-ps1, and adoptive transfer of Ag-specific Treg or Th2 cells restored protection against EAE in recipients. Upon assessment of each relative participant, functional inactivation of CD25 impaired PLP:OVA-pσ1's protective capacity, triggering TGF-β-mediated inflammation; however, concomitant inactivation of TGF-β and CD25 reestablished PLP:OVA-pσ1-mediated protection by IL-28-producing FoxP3 ⁺CD25^-CD4⁺ T cells. Thus, pσ1-based therapy can resolve EAE independently of or dependently upon CD25 and assigns IL-28 as an alternative therapy for autoimmunity.