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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3757-3766.
Prepublished online as a Blood First Edition Paper on January 16, 2007; DOI 10.1182/blood-2006-07-037655.
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Submitted July 26, 2006
Accepted December 30, 2006
Activation of the Hedgehog signaling pathway in T lineage cells inhibits TCR repertoire selection in the thymus and peripheral T cell activation
Nicola J Rowbotham, Ariadne L Hager-Theodorides, Marek Cebecauer, Divya K Shah, Ekati Drakopoulou, Julian Dyson, Susan V Outram, and Tessa Crompton*
Division of Cell and Molecular Biology, Imperial College London, London, United Kingdom
Section of Molecular and Cellular Medicine, Imperial College London, London, United Kingdom
Dept of Immunology, Imperial College London, London, United Kingdom
* Corresponding author; email: t.crompton{at}imperial.ac.uk.
TCR signal strength is involved in many cell fate decisions in the T cell lineage. Here we show that transcriptional events induced by Hedgehog signaling reduced TCR signal strength in mice. Activation of Hh signaling in thymocytes in vivo by expression of a transgenic transcriptional-activator form of Gli2 (Gli2 N2) changed the outcome of TCR ligation at many stages of thymocyte development, allowing self-reactive cells to escape clonal deletion; reducing transgenic TCR mediated positive selection; reducing the ratio of CD4:CD8 SP cells; and reducing cell surface CD5 expression. In contrast, in the Shh-/- thymus the ratio of CD4:CD8 cells, and both positive and negative selection of a transgenic TCR were increased, demonstrating that Shh does indeed influence TCR repertoire selection and the transition from DP to SP cell in a physiological situation. In peripheral T cells, Gli2N2 expression attenuated T cell activation and proliferation, by a mechanism upstream of ERK-phosphorylation.
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