Sonic Hedgehog regulates thymic epithelial cell differentiation

Article


Saldaña, J., Solanki, Anisha, Lau, Ching-In, Sahni, Hemant, Ross, Susan, Furmanski, Anna L., Ono, Masahiro, Holländer, Georg and Crompton, Tessa 2016. Sonic Hedgehog regulates thymic epithelial cell differentiation. Journal of Autoimmunity. 68 (April), pp. 86-97.
AuthorsSaldaña, J., Solanki, Anisha, Lau, Ching-In, Sahni, Hemant, Ross, Susan, Furmanski, Anna L., Ono, Masahiro, Holländer, Georg and Crompton, Tessa
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.

KeywordsThymic epithelium; Morphogen; Sonic hedgehog; T cell; MHCII; mTEC; cTEC
JournalJournal of Autoimmunity
Journal citation68 (April), pp. 86-97
ISSN0896-8411
1095-9157
Year2016
PublisherElsevier for Academic Press
Publisher's version
License
CC BY
Digital Object Identifier (DOI)doi:10.1016/j.jaut.2015.12.004
Publication dates
Print06 Jan 2016
Publication process dates
Deposited31 Jan 2017
Accepted16 Dec 2015
FunderMedical Research Council (MRC)
Biotechnology and Biological Sciences Research Council (BBSRC)
Wellcome Trust
Medical Research Council
Biotechnology and Biological Sciences Research Council
Wellcome Trust
National Institute for Health Research
Great Ormond Street Hospital for Children
University College London
Asthma UK
Child Health Research Action Trust
Copyright information© 2016 The Authors. Published by Elsevier Ltd.
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