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ß Thymopoiesis1
Department of Immunology, Duke University Medical Center, Durham, NC 27710
TCR gene rearrangement and expression are central to the
development of clonal T lymphocytes. The pre-TCR complex provides the
first signal instructing differentiation and proliferation events
during the transition from
CD4-CD8-TCR- double negative
(DN) stage to CD4+CD8+ double positive (DP)
stage. How the pre-TCR signal leads to downstream gene expression is
not known. HeLa E-box binding protein (HEB), a basic helix-loop-helix
transcription factor, is abundantly detected in thymocytes and is
thought to regulate E-box sites present in many T cell-specific gene
enhancers, including TCR-
, TCR-ß, and CD4. Targeted disruption of
HEB results in a 5- to 10-fold reduction in thymic cellularity that can
be accounted for by a developmental block at the DN to DP stage
transition. Specifically, a dramatic increase in the
CD4low/-CD8+CD5lowHSA+TCRlow/-
immature single positive population and a concomitant decrease in the
subsequent DP population are observed. Adoptive transfer test shows
that this defect is cell-autonomous and restricted to the ß T cell
lineage. Introduction of an ß TCR transgene into the
HEBko/ko background is not sufficient to rescue the
developmental delay. In vivo CD3 cross-linking analysis of thymocytes
indicates that TCR signaling pathway in the HEBko/ko mice
appears intact. These findings suggest an essential function of HEB in
early T cell development, downstream or parallel to the pre-TCR
signaling pathway.
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