Repression of hedgehog signal transduction in T-lineage cells increases TCR-induced activation and proliferation.
Hedgehog proteins signal for differentiation, survival and proliferation of the earliest thymocyte progenitors, but their functions at later stages of thymocyte development and in peripheral T-cell function are controversial. Here we show that repression of Hedgehog (Hh) pathway activation in T-lineage cells, by expression of a transgenic repressor form of Gli2 (Gli2DeltaC2), increased T-cell differentiation and activation in response to TCR signalling. Expression of the Gli2DeltaC2 transgene increased differentiation from CD4(+)CD8(+) to single positive thymocyte, and increased peripheral T cell populations. Gli2DeltaC2 T-cells were hyper-responsive to activation by ligation of CD3 and CD28: they expressed cell surface activation markers CD69 and CD25 more quickly, and proliferated more than wild-type T-cells. These data show that Hedgehog pathway activation in thymocytes and T-cells negatively regulates TCR-dependent differentiation and proliferation. Thus, as negative regulators of TCR-dependent events, Hh proteins provide an environmental influence on T-cell fate.
Rowbotham
Nicola J
NJ
Immunobiology Unit, UCL Institute of Child Health, London, United Kingdom.
Furmanski
Anna L
AL
Hager-Theodorides
Ariadne L
AL
Ross
Susan E
SE
Drakopoulou
Ekati
E
Koufaris
Costas
C
Outram
Susan V
SV
Crompton
Tessa
T
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D005838:Genotype; D053823:Hedgehog Proteins / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D000075746:Zinc Finger Protein Gli2
D017931:DNA Primers; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D000075746:Zinc Finger Protein Gli2