Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation

• Published in: Blood 2007-05, Vol.109 (9), p.3757-3766
• Main Authors: Rowbotham, Nicola J., Hager-Theodorides, Ariadne L., Cebecauer, Marek, Shah, Divya K., Drakopoulou, Ekati, Dyson, Julian, Outram, Susan V., Crompton, Tessa
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD5 Antigens - immunology; CD5 Antigens - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases - immunology; Extracellular Signal-Regulated MAP Kinases - metabolism; Hedgehog Proteins - deficiency; Hedgehog Proteins - immunology; Hedgehog Proteins - metabolism; Immunobiology; Kruppel-Like Transcription Factors - deficiency; Kruppel-Like Transcription Factors - immunology; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - immunology; Mice; Mice, Transgenic; Organ Culture Techniques; Receptors, Antigen, T-Cell; Thymus Gland - growth & development; Thymus Gland - immunology; Zinc Finger Protein Gli2
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-07-037655

TCR signal strength is involved in many cell fate decisions in the T-cell lineage. Here, we show that transcriptional events induced by Hedgehog (Hh) 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\#916;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 single-positive (SP) cells; and reducing cell surface CD5 expression. In contrast, in the Shh\#8722;/\#8722; 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 double-positive (DP) to SP cell in a physiological situation. In peripheral T cells, Gli2\#916;N2 expression attenuated T-cell activation and proliferation, by a mechanism upstream of ERK phosphorylation.