Adoptive transfer of T regulatory cells induced by immature DC suppresses retinal damage in experimental autoimmune uveitis (EAU)

Abstract

Abstract: : Purpose:Murine experimental autoimmune uveitis (EAU) is a T–cell mediated disease that targets the retina and serves as a model for human posterior uveitis, a major sight–threatening disease. EAU is inducible in many species with uveitogenic retinal antigens or by adoptive transfer of retina–specific syngeneic CD4⁺ T cells. Jiang et al. (IOVS, 2003) showed that tolerance in EAU is mediated through presentation of autoantigen by immature dendritic cells (iDC).We hypothesized that iDC may prime naive T cells to become CD4⁺CD25⁺ T regulatory cells (Treg). Methods:Immature BMDC were generated, pulsed with IRBP peptide and injected subcutaneously into B10RIII mice. CD4⁺CD25⁺ T cells were isolated 72 hours later from the dLN and adoptively transferred into naive and splenectomized mice prior to immunization with retinal antigen. 16 days after immunization eyes were harvested for histologic evaluation of the degree of disease present. Flow cytometry and cytokine analyses were performed to characterize both dLN cells and CD4⁺CD25⁺ T cells. Results:CD4⁺CD25⁺GITR⁺ cells are upregulated within 72 hours in dLN following injection of iDC. The cytokine profile of these iDC exhibits high amounts of IL–6 and no IL–12, IFNγ or TNFα. The predominant cytokine secreted by CD4⁺CD25⁺ Tregs purified from these dLN is IL–10. Tregs that are adoptively transferred prior to immunization with IRBP peptide markedly suppress disease, an effect potentiated in splenectomized animals. Conclusions:Adoptive transfer of tolerance is possible in the EAU model by Treg induced by iDC. The spleen appears to have a downmodulatory effect on iDC–induced Treg function.

Keywords: uveitis–clinical/animal model • immunomodulation/immunoregulation • antigen presentation/processing