Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation

Rowbotham, Nicola J.; Hager-Theodorides, Ariadne L.; Cebecauer, Marek; Shah, Divya; Drakopoulou, Ekati; Dyson, Julian; Outram, Susan V.; Crompton, Tessa

doi:10.1182/blood-2006-07-037655

Cited by 76 publications

(162 citation statements)

References 45 publications

(72 reference statements)

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“…In the thymus, SHH is a regulator of T-cell differentiation and T-cell receptor repertoire selection. 4,21,22 In lymph nodes, Sacedon et al 4 found that SHH is produced by follicular dendritic cells and that germinal center B cells express PTCH and SMO, components of the SHH receptor, suggesting that germinal center B cells are targets of SHH ligand produced by follicular dendritic cells. These authors also showed in vitro that SHH inhibition induces apoptosis in germinal center B cells, and that addition of exogenous SHH rescues germinal center B cells from Fas-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

et al. 2009

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Dysregulation of the sonic hedgehog (SHH) signaling pathway has been shown in several cancer types, but has not been explored in diffuse large B-cell lymphoma. We assessed 67 cases of diffuse large B-cell lymphoma for expression of SHH (ligand), GLI1, GLI2 and GLI3 (transcriptional effectors of SHH signaling), and the ATPbinding cassette (ABC)G2 (a downstream target of SHH signaling), using immunohistochemistry. For comparison, we assessed the expression levels of these proteins in 28 cases of follicular lymphoma, 5 chronic lymphocytic leukemia/small lymphocytic lymphoma, and 5 reactive lymph nodes. In diffuse large B-cell lymphoma, SHH was expressed in 61 of 67 (91%) cases, GLI1 in 62 of 67 (93%), GLI2 in 41 of 56 (73%), and GLI3 in 22 of 56 (39%). Expression of ABCG2 was detected in 52 of 55 (95%) cases and was high in 15 (27%) cases. SHH expression positively correlated with expression levels of ABCG2 (P ¼ 0.05). Patients with diffuse large Bcell lymphoma with high ABCG2 expression showed significantly shorter overall survival (P ¼ 0.031) and failurefree survival (P ¼ 0.029) compared with patients with tumors with low or no expression of ABCG2. Diffuse large B-cell lymphomas expressed SHH, and GLI1, GLI2, and GLI3 more frequently and more intensely than cases of follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. In conclusion, our data show that SHH signaling proteins and ABCG2 are aberrantly expressed in diffuse large B-cell lymphoma and that ABCG2 expression has prognostic implications. These findings also provide evidence that dysregulation of the SHH pathway may be involved in the pathogenesis of diffuse large B-cell lymphoma.

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Section: Discussionmentioning

confidence: 99%

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

et al. 2009

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“…Components of the Hh signaling pathway, including the Gli proteins, are differentially expressed in adult thymocyte populations. 6,[19][20][21][22] In the fetal thymus, Gli3 is differentially expressed in DN cells, with expression in the DN1 population, down-regulation in the subsequent DN2 and DN3 stages, and highest expression in the DN4 population. 21 Thymocyte populations were FACS-sorted from E16.5 fetal thymi and transcription of Gli2 was analyzed by QRT-PCR ( Figure 1A).…”

Section: Gli2 Is Expressed Differentially In Fetal Dn Subsetsmentioning

confidence: 99%

“…Gli2-deficient embryos die before birth, 14 so we used mouse models in which Hh signaling is specifically repressed or activated in T-lineage cells, by transgenic expression of activator-only or repressor-only truncated forms of Gli2, under the control of the lck promotor. 13,20,26,32 Our earlier work showed that these transgenics were successful at up-regulating (Gli2⌬N 2 [constitutively active Hh signal]) or down-regulating (Gli2⌬C 2 [constitutive repressor of Hh signaling]) Hh target genes in T-lineage cells. However, our previous studies of the Gli2⌬N 2 and Gli2⌬C 2 thymi had focused on later stages of T-cell development, and relative differences in the proportion of the DP population were small and were effected by changes at the DP to SP transition.…”

Section: Hh Pathway Activation Impedes Reconstitution Of the Dp Pool mentioning

confidence: 99%

“…lckGli2⌬N 2 and lck-Gli2⌬C 2 transgenic mice were as described. 20,26 For hydrocortisone (HC) treatment, mice were injected intraperitoneally with 0.03 mg per gram of body weight HC (Sigma-Aldrich, St Louis, MO) in PB, and analyzed after 2 to 7 days. 27 The United Kingdom Home Office (London, United Kingdom) approved mouse studies.…”

Section: Micementioning

confidence: 99%

“…17 In the mouse thymus, Shh is expressed by some epithelial cells in the subcapsular region, medulla, and corticomedullary junction, and the molecules that allow a cell to respond to Shh are expressed by both lymphoid and stromal components. 1,6,[18][19][20][21][22][23] Analysis of mice mutant for Shh, Gli3, and Smo have shown that Hh signaling is necessary for efficient survival, proliferation, and differentiation of thymocytes at the transition from DN1 to DN2, 18,21,22 but the role of Hh signaling at the transition from DN to DP thymocytes is controversial. Different experimental approaches have produced conflicting results that have led to 3 different interpretations: that Hh is a negative regulator of the pre-TCR signal and differentiation to DP 6,21,24 ; that Shh is a positive regulator of the DN to DP transition 18 ; or that Hh signaling does not influence thymocyte differentiation after the DN2 stage.…”

Section: Introductionmentioning

confidence: 99%

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Sonic hedgehog negatively regulates pre-TCR–induced differentiation by a Gli2-dependent mechanism

Rowbotham

Hager-Theodorides

Furmanski

et al. 2009

Blood

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Hedgehog signaling regulates differentiation, survival, and proliferation of the earliest double-negative (DN) thymocytes, but its importance at later stages of T-cell development is controversial. Here we use loss-and gain-of-function mouse models to show that Shh, by signaling directly to the developing thymocyte, is a negative regulator of pre-TCR-induced differentiation from DN to double-positive (DP) cell. When hedgehog signaling was reduced, in the Shh ؊/؊ and Gli2 ؊/؊ thymus, or by T lineage-specific transgenic expression of a transcriptional-repressor form of Gli2 (Gli2⌬C 2 ), differentiation to DP cell after pre-TCR signal transduction was increased. In contrast, when Hh signaling was constitutively activated in thymocytes, by transgenic expression of a constitutive transcriptional-activator form of Gli2 (Gli2⌬N 2 ), the production of DP cells was decreased. Gene expression profiling showed that physiologic Hh signaling in thymocytes maintains expression of the transcription factor FoxA2 on pre-TCR signal transduction. (Blood. 2009;113:5144-5156)

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Role of Hedgehog signalling at the transition from double‐positive to single‐positive thymocyte

et al. 2011

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In the thymus, developing T cells receive signals that determine lineage choice, specificity, MHC restriction and tolerance to self-antigen. One way in which thymocytes receive instruction is by secretion of Sonic hedgehog (Shh) from thymic epithelial cells. We have previously shown that Hedgehog (Hh) signalling in the thymus decreases the CD4:CD8 single-positive (SP) thymocyte ratio. Here, we present data indicating that double-positive (DP) thymocytes are Hh-responsive and that thymocyte-intrinsic Hh signalling plays a role in modulating the production of CD4+ (SP4), CD8+ (SP8) and unconventional T-cell subsets. Repression of physiological Hh signalling in thymocytes altered the proportions of DP and SP4 cells. Thymocyte-intrinsic Hh-dependent transcription also attenuated both the production of mature SP4 and SP8 cells, and the establishment of peripheral T-cell compartments in TCR-transgenic mice. Additionally, stimulation or withdrawal of Hh signals in the WT foetal thymus impaired or enhanced upregulation of the CD4 lineage-specific transcription factor Gata3 respectively. These data together suggest that Hh signalling may play a role in influencing the later stages of thymocyte development.

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Activation of the Hedgehog signaling pathway in T-lineage cells inhibits TCR repertoire selection in the thymus and peripheral T-cell activation

Cited by 76 publications

References 45 publications

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-Cell lymphoma

Sonic hedgehog negatively regulates pre-TCR–induced differentiation by a Gli2-dependent mechanism

Role of Hedgehog signalling at the transition from double‐positive to single‐positive thymocyte

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