IL-28 Supplants Requirement for Treg Cells in Protein σ1-Mediated Protection against Murine Experimental Autoimmune Encephalomyelitis (EAE)

Veterinary Molecular Biology, Montana State University, Bozeman, Montana, United States of America.
PLoS ONE (Impact Factor: 3.23). 01/2010; 5(1):e8720. DOI: 10.1371/journal.pone.0008720
Source: PubMed


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.

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Available from: Javier Ochoa-Repáraz, May 01, 2014
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    • "OVA-pσ1 also failed to stimulate CD8+ T cells, a finding not previously described. In fact, OVA-pσ1 was found to be tolerogenic and stimulated the production of IL-10 [25]–[29] or TGF-β [26], [27] and suppressed IFN-γ and IL-17 [25]–[28]. Since OVA-pσ1(s) lacked the SABD, an immunostimulatory response was induced, suggesting the SABD also contributes to tolerance induction. "
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    ABSTRACT: Ovalbumin (OVA) genetically fused to protein sigma 1 (pσ1) results in tolerance to both OVA and pσ1. Pσ1 binds in a multi-step fashion, involving both protein- and carbohydrate-based receptors. To assess the relative pσ1 components responsible for inducing tolerance and the importance of its sialic binding domain (SABD) for immunization, modified OVA-pσ1, termed OVA-pσ1(short), was deleted of its SABD, but with its M cell targeting moiety intact, and was found to be immunostimulatory and enhanced CD4(+) and CD8(+) T cell proliferation. When used to nasally immunize mice given with and without cholera toxin (CT) adjuvant, elevated SIgA and serum IgG responses were induced, and OVA-pσ1(s) was more efficient for immunization than native OVA+CT. The immune antibodies (Abs) were derived from elevated Ab-forming cells in the upper respiratory tissues and submaxillary glands and were supported by mixed Th cell responses. Thus, these studies show that pσ1(s) can be fused to vaccines to effectively elicit improved SIgA responses.
    Full-text · Article · Apr 2012 · PLoS ONE
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    • "Nonetheless, these CD25 − CD4 + T cells may also be a T reg cell subset, albeit independent of Foxp3. Since IL-4 was produced by both T cell subsets, IL-4 may be acting to enhance their regulatory function, as others have suggested (Faria and Weiner, 2005; Skapenko et al., 2005; Ochoa-Repáraz et al., 2008; Rynda et al., 2010). The impact of these T reg cells was largely attributed to the fimbriae since the Salmonella vector exhibited much less capacity to promote the development and expansion of T reg cells and was clearly less capable of protecting against EAE. "
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