Faculty Collaboration Database

A threshold for central T cell tolerance to an inducible serum protein. J Immunol 2003 Mar 15;170(6):3007-14

Date

03/11/2003

Pubmed ID

12626554

DOI

10.4049/jimmunol.170.6.3007

Scopus ID

2-s2.0-0347297138 (requires institutional sign-in at Scopus site)   20 Citations

Abstract

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.

Author List

Haribhai D, Engle D, Meyer M, Donermeyer D, White JM, Williams CB

Author

Calvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Autoantigens
Cell Differentiation
Clone Cells
Epitopes, T-Lymphocyte
Gene Expression Regulation
Hemoglobins
Humans
Immunodominant Epitopes
Mice
Mice, Inbred AKR
Mice, Inbred C57BL
Mice, Transgenic
Molecular Sequence Data
Muramidase
Peptide Fragments
Recombinant Fusion Proteins
Repressor Proteins
Self Tolerance
T-Lymphocyte Subsets
Tetracycline
Thymus Gland
Transgenes
Transplantation Tolerance