Sonic Hedgehog regulates thymic epithelial cell differentiation

Saldaña, José Ignacio; Solanki, Anisha; Lau, Ching‐In; Sahni, Hemant; Ross, Scott R.; Furmanski, Anna L.; Ono, M.; Holländer, Georg A.; Crompton, Tessa

doi:10.1016/j.jaut.2015.12.004

Cited by 31 publications

(49 citation statements)

References 56 publications

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“…We confirmed this delayed epithelial maturation, particularly in EphB3¡/¡ thymuses, by analyzing functional cell markers, such as CD205 a lectin involved in antigen uptake and processing 35 that, in agreement with previous studies, 36 is detected at E14.5. At E14.5 and E15.5 mutant thymuses accumulate immature Ly51 C CD205 ¡ cells whereas the proportion of mature Ly51 C CD205 C cells decreases, especially in EphB3¡/¡ thymuses.…”

Section: Discussionsupporting

confidence: 91%

EphB receptors, mainly EphB3, contribute to the proper development of cortical thymic epithelial cells

2017

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EphB and their ligands ephrin-B are an important family of protein tyrosine kinase receptors involved in thymocyte-thymic epithelial cell interactions known to be key for the maturation of both thymic cell components. In the present study, we have analyzed the maturation of cortical thymic epithelium in EphB-deficient thymuses evaluating the relative relevance of EphB2 and EphB3 in the process. Results support a relationship between the epithelial hypocellularity of mutant thymuses and altered development of thymocytes, lower proportions of cycling thymic epithelial cells and increased epithelial cell apoptosis. Together, these factors induce delayed development of mutant cortical TECs, defined by the expression of different cell markers, i.e. Ly51, CD205, MHCII, CD40 and β5t. Furthermore, although both EphB2 and EphB3 are necessary for cortical thymic epithelial maturation, the relevance of EphB3 is greater since EphB3-/- thymic cortex exhibits a more severe phenotype than that of EphB2-deficient thymuses.

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Section: Discussionsupporting

confidence: 91%

EphB receptors, mainly EphB3, contribute to the proper development of cortical thymic epithelial cells

2017

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“…The Gli3 mutant fetal thymus has increased expression of the Hh target gene Gli1 in stroma ( Hager-Theodorides et al, 2009 ), indicating that, overall, Gli3 acts as a repressor of Hh pathway activation in the stroma. Since Gli3 can repress Shh expression by repression of an intermediate transcriptional activator of Shh in other tissues ( te Welscher et al, 2002 ), and Shh is the key Hh ligand expressed by TECs ( Outram et al, 2000 ; Rowbotham et al, 2007 ; Saldaña et al, 2016 ; Shah et al, 2004 ), we tested whether more Shh protein was present in the Gli3-deficient fetal thymus compared with WT by ELISA. Shh protein was significantly increased in Gli3 −/− compared with WT ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…During αβ T-cell development in the thymus, CD4 − CD8 − double-negative (DN) cells differentiate to CD4 + CD8 + double-positive (DP) cells, which give rise to both CD4 single-positive (SP4) and CD8 single-positive (SP8) populations. Gli3 is expressed in adult and fetal thymic epithelial cells (TECs) and fetal but not adult thymocytes, and Gli3 promotes pre-T-cell receptor (TCR)-induced differentiation from DN to DP cell, and negative selection of the TCR repertoire ( Barbarulo et al, 2016 ; Hager-Theodorides et al, 2005 , 2009 ; Saldaña et al, 2016 ). Here, we investigate Gli3 function during αβ T-cell development in the embryonic thymus at the transition from the DP to SP cell.…”

Section: Introductionmentioning

confidence: 99%

“…In the thymus, Shh is expressed by TECs in the medulla and corticomedullary junction, and is required for normal medullary TEC development and maturation ( El Andaloussi et al, 2006 ; Outram et al, 2000 ; Sacedón et al, 2003 ; Saldaña et al, 2016 ). TECs provide MHCpeptide ligands for developing thymocytes and are required for both positive and negative selection of the TCR repertoire ( Klein et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

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In the fetal thymus, Gli3 in thymic epithelial cells promotes thymocyte positive selection and differentiation by repression ofShh

Solanki¹,

Yánez²,

Ross³

et al. 2018

Development

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Gli3 is a Hedgehog (Hh)-responsive transcription factor that can function as a transcriptional repressor or activator. We show that Gli3 activity in mouse thymic epithelial cells (TECs) promotes positive selection and differentiation from CD4+ CD8+ to CD4+ CD8− single-positive (SP4) cells in the fetal thymus and that Gli3 represses Shh. Constitutive deletion of Gli3, and conditional deletion of Gli3 from TECs, reduced differentiation to SP4, whereas conditional deletion of Gli3 from thymocytes did not. Conditional deletion of Shh from TECs increased differentiation to SP4, and expression of Shh was upregulated in the Gli3-deficient thymus. Use of a transgenic Hh reporter showed that the Hh pathway was active in thymocytes, and increased in the Gli3-deficient fetal thymus. Neutralisation of endogenous Hh proteins in the Gli3−/− thymus restored SP4 differentiation, indicating that Gli3 in TECs promotes SP4 differentiation by repression of Shh. Transcriptome analysis showed that Hh-mediated transcription was increased whereas TCR-mediated transcription was decreased in Gli3−/− thymocytes compared with wild type.

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“…TEC populations were isolated and sorted as described [13]. The data analysis was carried out as described [38].…”

Section: Methodsmentioning

confidence: 99%

The kinesin motor protein Kif7 is required for T-cell development and normal MHC expression on thymic epithelial cells (TEC) in the thymus

et al. 2017

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Kif7 is a ciliary kinesin motor protein that regulates mammalian Hedgehog pathway activation through influencing structure of the primary cilium. Here we show that Kif7 is required for normal T-cell development, despite the fact that T-cells lack primary cilia. Analysis of Kif7-deficient thymus showed that Kif7-deficiency increases the early CD44+CD25+CD4-CD8- thymocyte progenitor population but reduces differentiation to CD4+CD8+ double positive (DP) cell. At the transition from DP to mature T-cell, Kif7-deficiency selectively delayed maturation to the CD8 lineage. Expression of CD5, which correlates with TCR signal strength, was reduced on DP and mature CD4 and CD8 cells, as a result of thymocyte-intrinsic Kif7-deficiency, and Kif7-deficient T-cells from radiation chimeras activated less efficiently when stimulated with anti-CD3 and anti-CD28 in vitro. Kif7-deficient thymocytes showed higher expression of the Hedgehog target gene Ptch1 than WT, but were less sensitive to treatment with recombinant Shh, and Kif7-deficient T-cell development was refractory to neutralisation of endogenous Hh proteins, indicating that Kif7-deficient thymocytes were unable to interpret changes in the Hedgehog signal. In addition, Kif7-deficiency reduced cell-surface MHCII expression on thymic epithelial cells.

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Sonic Hedgehog regulates thymic epithelial cell differentiation

Cited by 31 publications

References 56 publications

EphB receptors, mainly EphB3, contribute to the proper development of cortical thymic epithelial cells

EphB receptors, mainly EphB3, contribute to the proper development of cortical thymic epithelial cells

In the fetal thymus, Gli3 in thymic epithelial cells promotes thymocyte positive selection and differentiation by repression ofShh

The kinesin motor protein Kif7 is required for T-cell development and normal MHC expression on thymic epithelial cells (TEC) in the thymus

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