Key Points
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Components of the hedgehog signalling pathway are expressed in human and mouse thymi by both stromal and lymphoid cells.
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Analysis of sonic hedgehog homologue (Shh)−/−, glioma-associated oncogene 3 (Gli3)−/− and conditional smoothened (Smo)−/− thymi revealed that SHH signalling is necessary for proliferation and survival of double-negative (DN) T cells and for efficient differentiation from DN1 to DN2.
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The function of hedgehog signalling at the transition from DN to double-positive (DP) cells is controversial, with experimental evidence supporting three possible interpretations: that hedgehog is a negative regulator of differentiation to the DP stage that counteracts the pre-TCR (T-cell receptor) signal; that SHH is a positive regulator of this transition; or, that hedgehog signalling has no influence on thymocyte differentiation after the DN2 stage. The evidence for these three hypotheses is discussed.
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Analysis of Shh−/− and Gli2ΔN2 transgenics revealed that SHH signalling influences TCR repertoire selection, CD4–CD8-lineage commitment and differentiation from DP to single-positive (SP) cells, most probably by reducing TCR signal strength.
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The involvement of SHH signalling in peripheral T-cell function is controversial with different experimental systems supporting three possible interpretations: that hedgehog is a negative regulator of peripheral T-cell activation; that hedgehog is necessary for efficient T-cell activation; or that hedgehog signalling is not involved in T-cell activation. Evidence in favour of these three different models is discussed.
Abstract
The production of mature functional T cells in the thymus requires signals from the thymic epithelium. Here, we review recent experiments showing that one way in which the epithelium controls the production of mature T cells is by the secretion of sonic hedgehog (SHH). We consider the increasing evidence that SHH-induced signalling is not only important for the differentiation and proliferation of early thymocyte progenitors, but also for modulating T-cell receptor signalling during repertoire selection, with implications for positive selection, CD4 versus CD8 lineage commitment, and clonal deletion of autoreactive cells. We also review the influence of hedgehog signalling in peripheral T-cell activation.
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Acknowledgements
We thank N. Rowbotham and E. Drakopoulou for helpful discussions. S.V.O. is funded by the BBSRC, and A.L.H.-T. is funded by the Wellcome Trust.
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Glossary
- Morphogen
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A protein that controls pattern formation by emanating from a localized source and creating a concentration gradient that regulates cell fate (proliferation, survival or differentiation) depending on the cell's position in the gradient.
- Patterning
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The process that coordinates progenitor-cell expansion and differentiation and establishes a non-random spatial formation of a tissue, organ or organism.
- Positive selection
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A process that leads to the survival of immature thymocytes that express a T-cell receptor that binds with an appropriate affinity to self MHC.
- Negative selection
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A process that results in the elimination of thymocytes expressing a T-cell receptor that binds with high affinity to self.
- Fetal thymus organ culture
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(FTOC). A system for culturing fetal thymi on a filter suspended over culture medium, which allows the growth of the organ for a longer period of time than the viability of the embryo allows and/or under various experimental conditions, for example by the addition of growth factors in the medium.
- Recombination-activating gene 1 (RAG 1) and RAG2 proteins
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Proteins that are both necessary for the recombination of the lymphocyte (T and B cell) receptor (TCR and BCR) loci. The recombination of T- and B-cell receptor loci is in turn necessary for the expression of functional TCR or BCR on T- or B-cell surface respectively and development of mature lymphocytes.
- β-selection
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A process leading, through a cell autonomous signalling cascade, to the proliferation and survival of thymocytes that have successfully recombined the β-chain of the T-cell receptor locus to express a functional pre-TCR on their cell surface.
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Crompton, T., Outram, S. & Hager-Theodorides, A. Sonic hedgehog signalling in T-cell development and activation. Nat Rev Immunol 7, 726–735 (2007). https://doi.org/10.1038/nri2151
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DOI: https://doi.org/10.1038/nri2151
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