2.50
Hdl Handle:
http://hdl.handle.net/10547/604700
Title:
Sonic Hedgehog regulates thymic epithelial cell differentiation
Authors:
Saldaña, José Ignacio; Solanki, Anisha; Lau, Ching-In; Sahni, Hemant; Ross, Susan; Furmanski, Anna L.; Ono, Masahiro; Holländer, Georg; Crompton, Tessa ( 0000-0002-8973-4021 )
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.
Affiliation:
University College London; University of Oxford
Citation:
Saldaña JI, Solanki A, Lau CI, Sahni H, Ross S, Furmanski AL, Ono M, Holländer G, Crompton T. (2016) 'Sonic Hedgehog regulates thymic epithelial cell differentiation'. Journal of Autoimmunity, 68, pp 86–97
Publisher:
Elsevier
Journal:
Journal of Autoimmunity
Issue Date:
Jan-2016
URI:
http://hdl.handle.net/10547/604700
DOI:
10.1016/j.jaut.2015.12.004
PubMed ID:
26778835
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S0896841115300585
Type:
Article
Language:
en
ISSN:
0896-8411
Sponsors:
This work was funded by the MRC, BBSRC and Wellcome Trust, and supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. AF was supported by Asthma UK; HS by the Child Health Research Action Trust; and AS and TC by Great Ormond Street Hospital Children's Charity. The authors have no conflicting financial interests.
Appears in Collections:
Biomedical Science

Full metadata record

DC FieldValue Language
dc.contributor.authorSaldaña, José Ignacioen
dc.contributor.authorSolanki, Anishaen
dc.contributor.authorLau, Ching-Inen
dc.contributor.authorSahni, Hemanten
dc.contributor.authorRoss, Susanen
dc.contributor.authorFurmanski, Anna L.en
dc.contributor.authorOno, Masahiroen
dc.contributor.authorHolländer, Georgen
dc.contributor.authorCrompton, Tessaen
dc.date.accessioned2016-04-07T09:01:20Zen
dc.date.available2016-04-07T09:01:20Zen
dc.date.issued2016-01en
dc.identifier.citationSaldaña JI, Solanki A, Lau CI, Sahni H, Ross S, Furmanski AL, Ono M, Holländer G, Crompton T. (2016) 'Sonic Hedgehog regulates thymic epithelial cell differentiation'. Journal of Autoimmunity, 68, pp 86–97en
dc.identifier.issn0896-8411en
dc.identifier.pmid26778835en
dc.identifier.doi10.1016/j.jaut.2015.12.004en
dc.identifier.urihttp://hdl.handle.net/10547/604700en
dc.description.abstractSonic 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.en
dc.description.sponsorshipThis work was funded by the MRC, BBSRC and Wellcome Trust, and supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. AF was supported by Asthma UK; HS by the Child Health Research Action Trust; and AS and TC by Great Ormond Street Hospital Children's Charity. The authors have no conflicting financial interests.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0896841115300585en
dc.rightsArchived with thanks to Journal of Autoimmunityen
dc.subjectMHCIIen
dc.subjectMorphogenen
dc.subjectSonic Hedgehogen
dc.subjectT cellen
dc.subjectThymic epitheliumen
dc.subjectcTECen
dc.subjectmTECen
dc.subjectC550 Immunologyen
dc.titleSonic Hedgehog regulates thymic epithelial cell differentiationen
dc.typeArticleen
dc.contributor.departmentUniversity College Londonen
dc.contributor.departmentUniversity of Oxforden
dc.identifier.journalJournal of Autoimmunityen
dc.description.noteOpen Access funded by Medical Research Council Under a Creative Commons licenseen

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