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 Blood, 21 May 2009, Vol. 113, No. 21, pp. 5144-5156.
Prepublished online as a Blood First Edition Paper on March 9, 2009; DOI 10.1182/blood-2008-10-185751.

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IMMUNOBIOLOGY

Sonic hedgehog negatively regulates pre-TCR–induced differentiation by a Gli2-dependent mechanism

Nicola J. Rowbotham1, Ariadne L. Hager-Theodorides1, Anna L. Furmanski1, Susan E. Ross1, Susan V. Outram1, Johannes T. Dessens2, and Tessa Crompton1

1 Immunobiology Unit, Univeristy College London Institute of Child Health, London; and 2 Department of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom

Hedgehog signaling regulates differentiation, survival, and proliferation of the earliest double-negative (DN) thymocytes, but its importance at later stages of T-cell development is controversial. Here we use loss- and gain-of-function mouse models to show that Shh, by signaling directly to the developing thymocyte, is a negative regulator of pre-TCR–induced differentiation from DN to double-positive (DP) cell. When hedgehog signaling was reduced, in the Shh–/– and Gli2–/– thymus, or by T lineage–specific transgenic expression of a transcriptional-repressor form of Gli2 (Gli2{Delta}C2), differentiation to DP cell after pre-TCR signal transduction was increased. In contrast, when Hh signaling was constitutively activated in thymocytes, by transgenic expression of a constitutive transcriptional-activator form of Gli2 (Gli2{Delta}N2), the production of DP cells was decreased. Gene expression profiling showed that physiologic Hh signaling in thymocytes maintains expression of the transcription factor FoxA2 on pre-TCR signal transduction.


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A. L. Hager-Theodorides, A. L. Furmanski, S. E. Ross, S. V. Outram, N. J. Rowbotham, and T. Crompton
The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms
J. Immunol., September 1, 2009; 183(5): 3023 - 3032.
[Abstract] [Full Text] [PDF]


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