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Adaptable TCR Avidity Thresholds for Negative Selection¹

Milica Stojakovic^*, Laura I. Salazar-Fontana^*, Zohreh Tatari-Calderone^*, Vladimir P. Badovinac, Fabio R. Santori^2,, Damian Kovalovsky^¶, Derek Sant'Angelo^¶, John T. Harty and Stanislav Vukmanovic^3,*,

^* Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, Washington, DC 20010; Department of Pathology, Carver College of Medicine and Department of Microbiology, University of Iowa, Iowa City, IA 52242; Department of Pathology, Michael Heidelberger Division of Immunology, and New York University Cancer Center, New York University School of Medicine, New York, NY 10016; and ^¶ Laboratory of T Cell Immunobiology, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021

Central tolerance plays a significant role in preventing autoimmune diseases by eliminating T cells with high and intermediate avidity for self. To determine the manner of setting the threshold for deletion, we created a unique transgenic mouse strain with a diverse T cell population and globally increased TCR avidity for self-peptide/MHC complexes. Despite the adaptations aimed at reducing T cell reactivity (reduced TCR levels and increased levels of TCR signaling inhibitor CD5), transgenic mice displayed more severe experimental allergic encephalomyelitis and lupus. The numbers and activity of natural (CD4⁺CD25⁺) regulatory T cells were not altered. These findings demonstrate that the threshold for deletion is adaptable, allowing survival of T cells with higher avidity when TCR avidity is globally increased.

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 the National Institutes of Health Grants AI48837 and AI41573 (to S.V.) and AI42767 (to J.T.H.).

² Current address: Department of Pathology, Skirball Institute for Molecular Medicine and New York University Cancer Center, New York University School of Medicine, 550 First Avenue, New York, NY 10016.

³ Address correspondence and reprint requests to Dr. Stanislav Vukmanovic, Center for Cancer and Immunology Research, Children’s Research Institute, Children’s National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010-2970. E-mail address: svukmano{at}cnmc.org

⁴ Abbreviations used in this paper: β₂m, β₂-microglobulin; EAE, experimental allergic encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; NP, nuclear protein; WT, wild type.