A threshold for central T cell tolerance to an inducible serum protein.
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 (< or = 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 approximately 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.
Haribhai
Dipica
D
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Engle
Deborah
D
Meyer
Michelle
M
Donermeyer
David
D
White
J Michael
JM
Williams
Calvin B
CB
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis* / Q000097:blood* / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002999:Clone Cells; D018984:Epitopes, T-Lymphocyte / Q000097:blood / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006454:Hemoglobins / Q000235:genetics / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000097:blood / Q000235:genetics / Q000276:immunology; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009113:Muramidase / Q000097:blood / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D013752:Tetracycline / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000637:transplantation; D019076:Transgenes / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006454:Hemoglobins; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C079201:hemoglobin (64-76); C034811:tetracycline resistance-encoding transposon repressor protein; C066759:hen egg lysozyme peptide (46-61); D009113:Muramidase; D013752:Tetracycline