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A Threshold for Central T Cell Tolerance to an Inducible Serum Protein¹

Dipica Haribhai^*, Deborah Engle^2,, Michelle Meyer, David Donermeyer, J. Michael White and Calvin B. Williams^3,*

^* Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226; and Departments of Pediatrics and Pathology, Washington University School of Medicine, St. Louis, MO 63110

We report an inducible system of self Ag expression that examines the relationship between serum protein levels and central T cell tolerance. This transgenic approach is based on tetracycline-regulated expression of a secreted form of hen egg lysozyme, tagged with a murine hemoglobin (Hb) epitope. In the absence of the tetracycline-regulated transactivator, serum levels of the chimeric protein are extremely low (0.1 ng/ml) and the mice show partial tolerance to both Hb(64–76) and lysozyme epitopes. In the presence of the transactivator, expression increases to 1.5 ng/ml and the mice are completely tolerant. Partial tolerance was further investigated by crossing these mice to strains expressing transgenic TCRs. At the lowest Ag levels, 3.L2tg T cells (specific for Hb(64–76)/I-E^k) escape the thymus and 10% of CD4⁺ splenocytes express the 3.L2 TCR. In contrast, 3A9 T cells (specific for hen egg lysozyme(46–61)/I-A^k) are completely eliminated by negative selection. These data define a tolerogenic threshold for negative selection of Ag-specific T cells by circulating self proteins that are 100-fold more sensitive than previously demonstrated. They suggest that partial tolerance at extremely low levels of self Ag exposure is the result of a restricted repertoire of responding T cells, rather than a simple reduction in precursor frequency; tolerogenic thresholds are T cell specific.

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