| During T cell development within the thymus the immune system has developed several developmental checkpoints to ensure the elimination of T cells endowed with antigen receptors specific for self antigens. Although such a tight regulation exists, some autoreactive T cells escape and undergo the maturation process. The activation of those autoreactive T cells leads to the development of autoimmune diseases. The neonatal period has been considered as a window during which the encounter with antigens induces tolerance rather than immunity. Therefore, introduction with defined autoantigens; into neonates could be an attractive strategy to induce neonatal tolerance, preventing autoimmunity. The necessity of incomplete Freund's adjuvant, however, hampers its clinical application. Due to efficient antigenic delivery in the context of immunoglobulin (Ig) and long half life of Ig in vivo we hypothesized that Ig-mediated peptide delivery into neonates may replace the requirement of IFA, thereby inducing neonatal tolerance. For this aim, we expressed a dominant encephalitogenic peptide (PLP 139–151, PLP1) derived from proteolipid protein (PLP), a known autoantigen for experimental allergic encephalomyelitis (EAE), an animal model for human multiple sclerosis, in place of CDR3 region of Ig molecule. Peptide presentation by resulting Ig-PLP1 molecule was antigen specific and had great efficiency in T cell stimulation by 100–1000 fold. Neonatal injection with Ig-PLP1 conferred a resistance to EAE without the presence of IFA. The mechanism underlying such resistance included IL-4-driven lymph node deviation, and IFNγ-dependent splenic anergy restorable by exogenous IFNγ or IL-12. Neonatal tolerance induced by Ig-PLP1 was unique and differentially regulated by the dose of antigen, the presence of adjuvant, and the number of injections. Furthermore, the dose of Ig-PLP1 displayed a quantitative variation in the outcome of tolerance, whereas adjuvant and the number of injections had a rather qualitative effect on the neonatal tolerance. Lastly we demonstrated that splenic cells from Ig-PLP1 tolerized mice displayed an anergic phenotype by the inability to upregulate IL-2 receptor α chain (CD25), which is responsible for responsiveness to IL-2. In addition, this defect in CD25 expression by splenic cells was shown to be critical in order to maintain long-lasting persistence of Ig-PLP1 mediated neonatal tolerance. |
