Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation.
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 (Gli2DeltaN(2)) 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(-/-) 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, Gli2DeltaN(2) expression attenuated T-cell activation and proliferation, by a mechanism upstream of ERK phosphorylation.
Rowbotham
Nicola J
NJ
Division of Cell and Molecular Biology, Imperial College London, South Kensington Campus, London, UK.
Hager-Theodorides
Ariadne L
AL
Cebecauer
Marek
M
Shah
Divya K
DK
Drakopoulou
Ekati
E
Dyson
Julian
J
Outram
Susan V
SV
Crompton
Tessa
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018956:CD5 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D053823:Hedgehog Proteins / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D011948:Receptors, Antigen, T-Cell; D013950:Thymus Gland / Q000254:growth & development / Q000276:immunology*; D000075746:Zinc Finger Protein Gli2
D018956:CD5 Antigens; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D011948:Receptors, Antigen, T-Cell; C465570:Shh protein, mouse; D000075746:Zinc Finger Protein Gli2; D048049:Extracellular Signal-Regulated MAP Kinases