Natural and induced regulatory T cells.

Mucosal antigen delivery can induce tolerance, as shown by suppression of subsequent responses to antigen. Our previous work showed that both intranasal and oral routes of antigen delivery were effective but indicated that the intranasal route might be more reliable. Intranasal peptide administration induced cells that could mediate bystander suppression of responses to associated antigenic epitopes. Here, we discuss further investigation into the nature of intranasal, peptide-induced tolerance. Cells from mice treated with intranasal peptide became anergic and shut down secretion of cytokines such as IL-2, but still secreted IL-10. This latter cytokine was required for suppression of immune responses in vivo even though suppression of responses in vitro was IL-10 independent. Intranasal peptide induced a subset of CD25(-), CTLA-4(+) regulatory cells that suppressed naive cell function in vitro and in vivo. We provide evidence that these cells arise from CD25(-) precursors and differentiate independently from natural CD25(+) regulatory cells. IL-10-secreting regulatory cells are also found in the peripheral blood of humans and can be induced by soluble peptide administration. This route of tolerance induction offers promise as a means of antigen-specific immunotherapy of allergic and autoimmune conditions in humans.

Destructive processing by asparagine endopeptidase limits presentation of a dominant T cell epitope in MBP.

Little is known about the processing of putative human autoantigens and why tolerance is established to some T cell epitopes but not others. Here we show that a principal human HLA-DR2-restricted epitope--amino acids 85-99 of myelin basic protein, MBP(85-99)--contains a processing site for the cysteine protease asparagine endopeptidase (AEP). Presentation of this epitope by human antigen-presenting cells is inversely proportional to the amount of cellular AEP activity: inhibition of AEP in living cells greatly enhances presentation of the MBP(85-99) epitope, whereas overexpression of AEP diminishes presentation. These results indicate that central tolerance to this encephalitogenic MBP epitope may not be established because destructive processing limits its display in the thymus. Consistent with this hypothesis, AEP is expressed abundantly in thymic antigen-presenting cells.