Experimental allergic encephalomyelitis (EAE), an inflammatory disease within the central nervous system (CNS) is used as an animal model for human multiple sclerosis (MS). The involvement of the immune system in these diseases is beyond doubt and both EAE and MS manifest as a consequence of activation of myelin- reactive pathogenic T lymphocytes. Usually, T regulatory cells (Tregs), a subset of suppressive T lymphocytes, keep the myelin-specific pathogenic T cells in check and maintain peripheral tolerance. However, circumstances exist under which this control fails and autoimmunity transpires. To date much work has been done to demonstrate the suppressive function of Tregs. However, little is known regarding the development of Tregs and the circumstances under which they expand to counter autoimmunity. The long term objective of this proposal is to determine whether Tregs undergo selection and if they do, whether such selection is driven by the strength of T cell receptor (TCR)-ligand interactions. The hypothesis in this application postulates that Tregs undergo thymic selection and require rather high avidity for maturation. To test this hypothesis we propose to deliver altered peptides with degenerate TCR affinity for fetal presentation and test for fetal thymic Tregs selection and maturation and evaluate the consequences of such development on the peripheral expansion of Tregs in the offspring as well as their ability to modulate EAE. The SJL/J mouse expresses only the DM20 form of proteolipid protein (PLP) during fetal and neonatal life. DM20 is a mutant form of PLP missing the immunodominant PLP1 sequence corresponding to amino acid residues 139-151 of PLP. It has been shown that thymic negative selection against PLP1 is defective during the fetal/neonatal period. Immunoglobulins (Igs) can cross the maternal placenta and transfer from mother to fetus. Igs are also permissive for molecular grafting and expression of peptides within the heavy complementarily determining region-3 (CDR3). Herein, we propose to express PLP1 as well as PLP1-derived altered peptides on Igs and utilize the resulting Ig chimeras to deliver the peptides through the SJL/J maternal placenta and restore presentation during fetal life. Subsequently, we will evaluate the effect of such fetal presentation on Tregs selection, maturation, migration to the periphery and modulation of EAE.T regulatory cells (Tregs) represent a subset of suppressive cells that control peripheral tolerance and prevent the development of autoimmunity. Understanding how Tregs develop, mature, and carry out suppressive functions should impact the design of approaches to modulate autoimmunity. This proposal takes advantage of a unique peptide delivery system and a suitable mouse strain to investigate the development of Tregs. The study is highly significant and could impact the field of autoimmunity both at the level of basic science and clinical practice.
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