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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Regulation of T cell receptor (TCR) beta gene expression by CD3 complex signaling in immature thymocytes:

J Biro1, A Würch, A J Potocnik

  • 1Max-Planck-Institut für Immunbiologie, D-79108 Freiburg, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|March 31, 1999
PubMed

During alphabeta thymocyte development, clonotype-independent CD3 complexes are expressed at the cell surface before the pre-T cell receptor (TCR). Signaling through clonotype-independent CD3 complexes is required for expression of rearranged TCRbeta genes. On expression of a TCRbeta polypeptide chain, the pre-TCR is assembled, and TCRbeta locus allelic exclusion is established. We investigated the putative contribution of clonotype-independent CD3 complex signaling to TCRbeta locus allelic exclusion in mice single-deficient or double-deficient for CD3zeta/eta and/or p56(lck). These mice display defects in the expression of endogenous TCRbeta genes in immature thymocytes, proportional to the severity of CD3 complex malfunction. Exclusion of endogenous TCRbeta VDJ (variable, diversity, joining) rearrangements by a functional TCRbeta transgene was severely compromised in the single-deficient and double-deficient mutant mice. In contrast to wild-type mice, most of the CD25(+) double-negative (DN) thymocytes of the mutant mice failed to express the TCRbeta transgene, suggesting defective expression of the TCRbeta transgene similar to endogenous TCRbeta genes. In the mutant mice, a proportion of CD25(+) DN thymocytes that failed to express the transgene expressed endogenous TCRbeta polypeptide chains. Many double-positive cells of the mutant mice coexpressed endogenous and transgenic TCRbeta chains or more than one endogenous TCRbeta chain. The data suggest that signaling through clonotype-independent CD3 complexes may contribute to allelic exclusion of the TCRbeta locus by inducing the expression of rearranged TCRbeta genes in CD25(+) DN thymocytes.

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