A novel role for HEB downstream or parallel to the pre-TCR signaling pathway during alpha beta thymopoiesis.
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-alpha, TCR-beta, 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 alpha beta T cell lineage. Introduction of an alpha beta 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.
Barndt
R
R
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Dai
M F
MF
Zhuang
Y
Y
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D018257:Helix-Loop-Helix Motifs; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics; D007274:Injections, Intraperitoneal; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019076:Transgenes / Q000276:immunology
D000911:Antibodies, Monoclonal; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta; D015375:Receptors, Interleukin-2; D014157:Transcription Factors; C489532:Tcf12 protein, mouse