Tolerance induction by elimination of subsets of self-reactive thymocytes

A. M. Sponaas, P. D. Tomlinson, R. Schulz, J. Antoniou, P. Ize-Iyamu, A. M. Schmitt-Verhulst, A. L. Mellor

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Immature thymocytes expressing TCRs which confer reactivity to self-MHC molecules are subject to efficient elimination as a result of negative selection. Previously, we have identified a lineage of H-2Kb Tg mice, CD2Kb-3, which fails to reject skin grafts from mice expressing H-2Kb even though H-2Kb-specrfic cytotoxlc T cells can be generated in vitro. We now show that bone marrow derived cells are responsible for tolerance induction and that tolerance is acquired, at toast in part, by negative selection in CD2Kb-3 mice. Thymocytes expressing two different transgenic TCR (TCR-Tg) clonotypes conferring reactivity to H-2Kb are eliminated prior to the CD8+CD4+ stage of differentiation in double Tg (CD2Kb-3×TCR-Tg)F1 mice. As in other cases where thymocytes from TCR-Tg mice develop in the presence of deleting ligands, large numbers of TCR+ CD8-CD4- T cells accumulate in double Tg mice. However, these T cells fail to respond to H-2Kb in vitro but can be activated with immobilized anti-clonotyplc antibody. Consequently, thymocytes expressing these types of TCR molecules represent a fraction of H-2Kb-reactive thymocytes which are unable to mature into T cells capable of mounting H-2Kb-specific cytotoxic responses. Presumably, precursors of H-2Kb-spicific cytotoxlc T cells found in the periphery of CD2Kb-3 mice express a distinct repertoire of TCR molecules conferring reactivity to H-2Kb. We consider potential explanations to account for this discrepancy and their wider implications, including the possibility that the repertoire of thymocytea able to recognize setf-H-2Kb molecules In CD2K b-3 mice is divided into distinct subsets; those which are, and those which are not, subject to negative selection.

Original languageEnglish (US)
Pages (from-to)1593-1604
Number of pages12
JournalInternational Immunology
Volume6
Issue number10
DOIs
StatePublished - Jan 1 1994

Keywords

  • Negative selction
  • Thymocytes
  • Tolerance
  • Transgenic mice

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Sponaas, A. M., Tomlinson, P. D., Schulz, R., Antoniou, J., Ize-Iyamu, P., Schmitt-Verhulst, A. M., & Mellor, A. L. (1994). Tolerance induction by elimination of subsets of self-reactive thymocytes. International Immunology, 6(10), 1593-1604. https://doi.org/10.1093/intimm/6.10.1593