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A critical lineage-nonspecific role for pTalpha in mediating allelic and isotypic exclusion in TCRbeta-transgenic mice.

Authors
Journal
European Journal of Immunology
0014-2980
Publisher
Wiley Blackwell (John Wiley & Sons)
Publication Date
Volume
37
Issue
11
Identifiers
DOI: 10.1002/eji.200737456
Keywords
  • Alleles
  • Animals
  • Blotting
  • Western
  • Cell Lineage/Immunology
  • Flow Cytometry
  • Gene Rearrangement
  • Beta-Chain T-Cell Antigen Receptor
  • Genes
  • T-Cell Receptor Beta
  • Hematopoietic Stem Cells/Immunology
  • Hematopoietic Stem Cells/Metabolism
  • Membrane Glycoproteins/Genetics
  • Mice
  • Mice
  • Inbred C57Bl
  • Mice
  • Knockout
  • Receptors
  • Antigen
  • T-Cell
  • Alpha-Beta/Genetics
  • Receptors
  • Antigen
  • T-Cell
  • Alpha-Beta/Metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
Disciplines
  • Biology

Abstract

Although it is well established that early expression of TCRbeta transgenes in the thymus leads to efficient inhibition of both endogenous TCRbeta and TCRgamma rearrangement (also known as allelic and "isotypic" exclusion, respectively) the role of pTalpha in these processes remains controversial. Here, we have systematically re-evaluated this issue using three independent strains of TCRbeta-transgenic mice that differ widely in transgene expression levels, and a sensitive intracellular staining assay that detects endogenous TCRVbeta expression in individual immature thymocytes. In the absence of pTalpha, both allelic and isotypic exclusion were reversed in all three TCRbeta-transgenic strains, clearly demonstrating a general requirement for pre-TCR signaling in the inhibition of endogenous TCRbeta and TCRgamma rearrangement. Both allelic and isotypic exclusion were pTalpha dose dependent when transgenic TCRbeta levels were subphysiological. Moreover, pTalpha-dependent allelic and isotypic exclusion occurred in both alphabeta and gammadelta T cell lineages, indicating that pre-TCR signaling can potentially be functional in gammadelta precursors. Finally, levels of endogenous RAG1 and RAG2 were not down-regulated in TCRbeta-transgenic immature thymocytes undergoing allelic or isotypic exclusion. Collectively, our data reveal a critical but lineage-nonspecific role for pTalpha in mediating both allelic and isotypic exclusion in TCRbeta-transgenic mice.

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