Ligand density determines the efficiency of negative selection in the thymus
- Author(s)
- Romermann, D; Heath, WR; Allison, J; Bayer, B; Sorge, Y; Miller, JFAP; Hoffmann, MW;
- Details
- Publication Year 2001-07-27,Volume 72,Issue #2,Page 305-311
- Journal Title
- TRANSPLANTATION
- Publication Type
- Journal Article
- Abstract
- To study the influence of antigen density on the efficiency of negative selection in the thymus, MHC class I (H-2K(b), K-b) transgenic mice were generated, which expressed a K-b transgene under the control of its natural promoter at 33% (Kb-lo) or 150% (Kb-hi) the surface density of K-b in C57BL/6 (B6, H-2(b)) mice. These mice were crossed to anti-Kb T-cell receptor (Des-TCR) transgenic mice. In Des-TCRxK(b-hi) double transgenic mice, Des-TCR bearing T cells were completely eliminated during thymocyte maturation. In contrast, in Des-TCRxK(b-lo) double transgenic mice, two populations of Des-TCR T cells were evident, which either expressed the Des-TCR at intermediate density in the absence of CD8 (Des-TCR(int)CD8(-)) or expressed both the Des-TCR and CD8 at low density (Des-TCR(lo)CD8(lo)). In the thymus of both types of double transgenic mice, no Des-TCR(+)CD4(+)CD8(+) thymocytes were detected, suggesting that deletion of Des-TCR cells occurred before the CD4(+)CD8(+) stage. Because only very few Des-TCR+ thymocytes were found in Des-TCRxK(b-hi) transgenic mice, deletion of these T cells apparently occurred upon expression of the Des-TCR. By contrast, Des-TCRxK(b-lo) transgenic mice showed distinct populations of Des-TCR(int)CD4(-)8(-) and Des-TCR(int)CD8(lo) thymocytes, suggesting that expression of the CD8 coreceptor was required to allow negative selection to proceed. Functional analyses showed that sublethally irradiated Des-TCRxK(b-lo) double transgenic mice were protected from lethal graft-versus-host disease by injected Des-TCR lymph node cells.
- Publisher
- LIPPINCOTT WILLIAMS & WILKINS
- Keywords
- RECEPTOR TRANSGENIC MICE; CLASS-I GENE; T-CELLS; MONOCLONAL-ANTIBODIES; TOLERANCE INDUCTION; POSITIVE SELECTION; EXPRESSION; ANTIGEN; DIFFERENTIATION; INTERNALIZATION
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Creation Date: 2001-07-27 12:00:00