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Reference: Saldana, JI, Solanki, A, Lau, CI et al., (2016). Sonic Hedgehog regulates thymic epithelial cell differentiation. Journal of Autoimmunity.Citable link to this page:

 

Sonic Hedgehog regulates thymic epithelial cell differentiation

Abstract: Sonic Hedgehog (Shh) is expressed in the thymus, where it regulates T cell development. Here we investigated the influence of Shh on thymic epithelial cell (TEC) development. Components of the Hedgehog (Hh) signalling pathway were expressed by TEC, and use of a Gli Binding Site-green fluorescence protein (GFP) transgenic reporter mouse demonstrated active Hh-dependent transcription in TEC in the foetal and adult thymus. Analysis of Shh-deficient foetal thymus organ cultures (FTOC) showed that Shh is required for normal TEC differentiation. Shh-deficient foetal thymus contained fewer TEC than wild type (WT), the proportion of medullary TEC was reduced relative to cortical TEC, and cell surface expression of MHC Class II molecules was increased on both cortical and medullary TEC populations. In contrast, the Gli3-deficient thymus, which shows increased Hh-dependent transcription in thymic stroma, had increased numbers of TEC, but decreased cell surface expression of MHC Class II molecules on both cortical and medullary TEC. Neutralisation of endogenous Hh proteins in WT FTOC led to a reduction in TEC numbers, and in the proportion of mature Aire-expressing medullary TEC, but an increase in cell surface expression of MHC Class II molecules on medullary TEC. Likewise, conditional deletion of Shh from TEC in the adult thymus resulted in alterations in TEC differentiation and consequent changes in T cell development. TEC numbers, and the proportion of mature Aire-expressing medullary TEC were reduced, and cell surface expression of MHC Class II molecules on medullary TEC was increased. Differentiation of mature CD4 and CD8 single positive thymocytes was increased, demonstrating the regulatory role of Shh production by TEC on T cell development. Treatment of human thymus explants with recombinant Shh or neutralising anti-Shh antibody indicated that the Hedgehog pathway is also involved in regulation of differentiation from DP to mature SP T cells in the human thymus.

Peer Review status:Peer reviewedPublication status:In pressVersion:Publisher's version Funder: Medical Research Council   Funder: Biotechnology and Biological Sciences Research Council   Funder: Wellcome Trust   Funder: National Institute for Health Research   Notes:Under a Creative Commons license.

Bibliographic Details

Publisher: Elsevier

Publisher Website: http://www.elsevier.com/

Journal: Journal of Autoimmunitysee more from them

Publication Website: http://www.journals.elsevier.com/journal-of-autoimmunity/

Issue Date: 2016Identifiers

Urn: uuid:c93c4630-a368-4511-b488-6d677b06f276

Source identifier: 581080

Doi: https://doi.org/10.1016/j.jaut.2015.12.004

Issn: 1095-9157 Item Description

Type: Journal article;

Version: Publisher's versionKeywords: thymic epithelium morphogen Sonic hedgehog T cell MHCII mTEC cTEC Tiny URL: pubs:581080

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Author: Saldana, JI - - - Solanki, A - - - Lau, CI - - - Sahni, H - - - Ross, S - - - Furmanski, AL - - - Ono, M - - - Hollander, GAP - i

Source: https://ora.ox.ac.uk/objects/uuid:c93c4630-a368-4511-b488-6d677b06f276



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