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Mouse Lysozyme-M Knockout Mice Reveal How the Self-Determinant Hierarchy Shapes the T Cell Repertoire against This Circulating Self Antigen in Wild-Type Mice¹

Pratima Sinha^*, Howard H. Chi^*, Hong R. Kim^*, Björn E. Clausen, Brian Pederson, Eli E. Sercarz^,, Irmgard Forster^¶ and Kamal D. Moudgil^2,*

^* Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; La Jolla Institute for Allergy and Immunology, San Diego, CA 92121; Torrey Pines Institute for Molecular Studies, San Diego, CA 92121; and ^¶ Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Munich, Germany

We have studied T cell tolerance to defined determinants within ML-M using wild-type (WT; ML-M^+/+) and LysMcre (ML-M^–/–) C3H (H-2^k) mice to determine the relative contribution of ML-M-derived epitopes vs those from other self Ags in selection of the ML-M-specific T cell repertoire. ML-M was totally nonimmunogenic in WT mice, but was rendered immunogenic in LysMcre mice. Most of the response to ML-M in LysMcre mice was directed to the immunodominant determinant region 105–119. This determinant is spontaneously displayed (without adding exogenous ML-M) by macrophages of WT, but not LysMcre, mice and is stimulatory for peptide 105–119 (p105–119)-primed T cells. Moreover, neonatal tolerization of LysMcre mice with p105–119 or ML-M abrogated the T cell response to subsequent challenge with ML-M or p105–119. Furthermore, p95–109 and p110–125 of ML-M were immunogenic in LysMcre mice, but not in WT mice, thereby representing subdominant, tolerance-inducing epitopes of ML-M. As expected, the T cell repertoire to cryptic ML determinants in WT mice was also intact in LysMcre mice. Furthermore, the pattern of response to the related homologue of ML-M, hen eggwhite lysozyme, was similar in these two groups of mice. Thus, several codominant T cell determinants within ML-M contribute significantly to tolerance induction, and the anti-cryptic T cell repertoire to ML-M was positively selected on non-ML-M self ligands. These results reveal that the induction of self tolerance to a multideterminant protein follows the quantitative hierarchy of self-determinant expression and are of relevance in understanding the pathogenesis of autoimmunity.

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