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Efficient induction of CD25- iTreg by co-immunization requires strongly antigenic epitopes for T cells

DOI: 10.1186/1471-2172-12-27

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In the present study, we demonstrated the requirement of highly antigenic epitopes for CD25- iTreg induction. Firstly, we showed that the induction of CD25- iTreg by tolerogenic DC can be blocked by anti-MHC-II antibody. Next, both the number and the suppressive activity of CD25- iTreg correlated positively with the overt antigenicity of an epitope to activate T cells. Finally, in a mouse model of dermatitis, highly antigenic epitopes derived from a flea allergen not only induced more CD25- iTreg, but also more effectively prevented allergenic reaction to the allergen than did weakly antigenic epitopes.Our data thus indicate that efficient induction of CD25- iTreg requires highly antigenic peptide epitopes. This finding suggests that highly antigenic epitopes should be used for efficient induction of CD25- iTreg for clinical applications such as flea allergic dermatitis.The inducible regulatory T cells, or iTreg, differ from the naturally regulatory T cells (nTreg) in that the former are generated in the periphery through encounter with environmental antigens. It is also believed that iTreg play non-overlapping roles, relative to nTreg, in regulating peripheral tolerance [1-3]. Most iTreg reported to date have been CD25+ cells (CD4+CD25+Foxp3+), and it is well established that their induction requires suboptimal stimulation of the T cell receptor (TCR) and cytokines TGF-β and IL-2 [3]. The CD25+ iTreg thus appear to derive primarily from weakly stimulated CD4+ T cells.We previously identified a different subset of iTreg in mice that is CD25- (CD4+CD25-Foxp3+ and IL-10+TGF-beta+IFN-γ-). The CD25- iTreg were induced after co-immunization using a protein antigen and a DNA vaccine encoding the same antigen [4-7]. Unlike that of the CD25+ iTreg, the induction of the CD25- iTreg involved the generation of CD40low IL-10high tolerogenic dendritic cells (DCs), which in turn stimulated CD25- iTreg in an antigen-specific manner [4]. We further showed in mouse models that this

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