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Blood, 5 March 2009, Vol. 113, No. 10, pp. 2217-2228.
Prepublished online as a Blood First Edition Paper on December 23, 2008; DOI 10.1182/blood-2008-03-144840.
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Submitted March 12, 2008
Accepted November 16, 2008
Indian hedgehog (Ihh) both promotes and restricts thymocyte differentiation
Susan V Outram, Ariadne L. Hager-Theodorides, Divya K. Shah, Nicola J. Rowbotham, Ekati Drakopoulou, Susan E. Ross, Beate Lanske, Johannes T. Dessens, and Tessa Crompton*
Immunobiology Unit, UCL Institute of Child Health, London, United Kingdom
Sunnybrook Research Institute, Toronto, ON, Canada
Department of Developmental Biology, HSDM, Boston, MA, United States
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
* Corresponding author; email: t.crompton{at}ich.ucl.ac.uk.
We show that Ihh regulates T-cell development and homeostasis in both fetal and adult thymus, controlling thymocyte number. Fetal Ihh-/- thymi had reduced differentiation to DP cell and reduced cell numbers compared to WT littermates, and analysis of Ihh-/-Shh+/- embryos revealed a redundant function for Ihh, promoting the transition from DN1 to DN2. Surprisingly, fetal Ihh+/- thymi had increased thymocyte numbers and proportion of DP cells relative to WT, indicating that Ihh also negatively regulates thymocyte development. In vitro treatment of thymus explants with exogenous recombinant Hedgehog protein promoted thymocyte development in Ihh-/- thymi, but inhibited thymocyte development in Ihh+/-, confirming both positive and negative regulatory functions of Ihh. Analysis of Rag-/-Ihh+/- thymi, in which the pre-TCR signal may be simulated by treatment with anti-CD3 antibody, showed that Ihh promotes T-cell development prior to pre-TCR signaling, but negatively regulates T-cell development only after pre-TCR signaling has taken place. We show that ihh is most highly expressed by the DP population, and that Ihh produced by DP cells feeds back to negatively regulate the differentiation and proliferation of their DN progenitors. Thus, differentiation from DN to DP cell, and hence the size of the DP population is dependent on the concentration of Ihh in the thymus. Analysis of Ihh conditional knockout and heterozygote adult mice showed that Ihh also influences DP cell production and thymocyte number in the adult.
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