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CD4⁺CD25⁺ Regulatory T Cell Repertoire Formation Shaped by Differential Presentation of Peptides from a Self-Antigen¹

Joseph Larkin, III^2,*, Andrew L. Rankin^*, Cristina Cozzo Picca^*, Michael P. Riley^*, Scott A. Jenks, Andrea J. Sant and Andrew J. Caton^3,*

^* The Wistar Institute, Philadelphia, PA 19104; and Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642

We have used TCR transgenic mice directed to different MHC class II-restricted determinants from the influenza virus hemagglutinin (HA) to analyze how specificity for self-peptides can shape CD4⁺CD25⁺ regulatory T (Treg) cell formation. We show that substantial increases in the number of CD4⁺CD25⁺ Treg cells can occur when an autoreactive TCR directed to a major I-E^d-restricted determinant from HA develops in mice expressing HA as a self-Ag, and that the efficiency of this process is largely unaffected by the ability to coexpress additional TCR -chains. This increased formation of CD4⁺CD25⁺ Treg cells in the presence of the self-peptide argues against models that postulate selective survival rather than induced formation as mechanisms of CD4⁺CD25⁺ Treg cell formation. In contrast, T cells bearing a TCR directed to a major I-A^d-restricted determinant from HA underwent little or no selection to become CD4⁺CD25⁺ Treg cells in mice expressing HA as a self-Ag, correlating with inefficient processing and presentation of the peptide from the neo-self-HA polypeptide. These findings show that interactions with a self-peptide can induce thymocytes to differentiate along a pathway to become CD4⁺CD25⁺ Treg cells, and that peptide editing by DM molecules may help bias the CD4⁺CD25⁺ Treg cell repertoire away from self-peptides that associate weakly with MHC class II molecules.

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 AI59166, AI24541, and CA09140 from the National Institutes of Health, by the Lupus Foundation of Southeastern Pennsylvania, and by the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.

² Current address: Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611.

³ Address correspondence and reprint requests to Dr. Andrew J. Caton, The Wistar Institute, Room 262, 3601 Spruce Street, Philadelphia, PA 19104. E-mail address: caton{at}wistar.org

⁴ Abbreviations used in this paper: Treg, regulatory T; BM, bone marrow; HA, hemagglutinin; LN, lymph node; PR8, influenza virus A/PR/8/34; SF medium, serum-free supplemented IMDM.

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