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Fetal Exposure to High-Avidity TCR Ligand Enhances Expansion of Peripheral T Regulatory Cells¹

Ping Yu^2,*, Cara L. Haymaker^*, Rohit D. Divekar^*, Jason S. Ellis^*, John Hardaway^*, Renu Jain^*, Danielle M. Tartar^*, Christine M. Hoeman^*, Jason A. Cascio^*, Austin Ostermeier^* and Habib Zaghouani^3,*,

^* Department of Molecular Microbiology and Immunology and Department of Child Health, University of Missouri School of Medicine, Columbia, MO 65212

Lately, it has become clear that regulatory T cells (Tregs) play a major role in the maintenance of peripheral tolerance and control of autoimmunity. Despite these critical functions, the process underlying the development of Tregs remains largely undefined. Herein, altered peptide ligand (APL) variants derived from the proteolipid protein-1 (PLP1) epitope were expressed on immunoglobulins (Igs) and the resulting Ig-APLs were used to deliver the APLs from mother to fetus through the maternal placenta to influence thymic T cell selection. This delivery system was then adapted to the SJL/J mouse, a strain that expresses only the DM20 form of PLP, which lacks the dominant PLP1 epitope in the thymus during fetal and neonatal development. This model, which restores thymic T cell selection for PLP1, was then used to determine whether affinity plays a role in the development of Tregs. The findings show that fetal exposure to low-affinity peptide ligand was unable to drive development of Tregs while variants with higher affinity to the TCR resulted in significant seeding of the periphery with mature, naive Tregs. Thus, contrary to pathogenic T cells, Tregs require avid TCR-ligand interaction to undergo thymic development and maturation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants 2RO1 NS37406, RO1 NS057194, and RO1 AI48541 (to H.Z.) from the National Institutes of Health. J.S.E. and C.M.H. were supported by the predoctoral training grant (T32 GM08396) from National Institute of General Medical Sciences. D.M.T., J.A.C., and J.C.H. were supported by a life science fellowship from the University of Missouri.

² Current address: National Cancer Institute, Metabolism Branch, Bethesda, MD 20892.

³ Address correspondence and reprint requests to Dr. Habib Zaghouani, Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, M616 Medical Sciences Building, Columbia, MO 65212. E-mail address: zaghouanih{at}health.missouri.edu

⁴ Abbreviations used in this paper: agg, aggregated; APL, altered peptide ligand; EAE, experimental allergic encephalomyelitis; PLP, proteolipid protein; Treg, regulatory T cell; Tg, transgenic.

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