Repression of Hedgehog signal transduction in T-lineage cells increases TCR-induced activation and proliferation

Rowbotham, Nicola J.; Furmanski, Anna L.; Hager-Theodorides, Ariadne L.; Ross, Scott R.; Drakopoulou, Ekati; Koufaris, Costas; Outram, Susan V.; Crompton, Tessa

doi:10.4161/cc.7.7.5628

Cited by 37 publications

(72 citation statements)

References 20 publications

(35 reference statements)

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“…5, B and C). The reduction in TCR signaling observed is consistent with our previous findings in different knockout and transgenic systems (11,29) and may explain the presence of CD4SP thymocytes.…”

Section: Hytcrtggli3supporting

confidence: 81%

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The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms

Hager-Theodorides

Furmanski²,

Ross³

et al. 2009

The Journal of Immunology

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The Hedgehog (Hh) responsive transcription factor Gli3 is required for efficient thymocyte development in the fetus. In this study we show that Gli3, not detected in adult thymocytes, is expressed in the murine fetal and adult thymus stroma. PCR array analysis revealed Cxcl9, Rbp1, and Nos2 as novel target genes of Gli3. We show that Gli3 positively regulates the expression of these genes, most likely by suppressing an intermediate repressor. Deletion of autoreactive thymocytes depends on their interactions with the thymus stroma. Repression of the proapoptotic gene Nos2 in Gli3 mutants coincides with reduced apoptosis of double positive thymocytes undergoing negative selection in vitro and in vivo, and the production of autoreactive thymocytes. Taken together these data indicate that Gli3 controls thymocyte apoptosis and negative selection possibly via the regulation of Nos2. Defective Gli3 expression in the thymus stroma also resulted in decreased CD5 expression on mature thymocytes and inappropriate production of MHC class I-selected CD4+ cells, both consistent with reduced TCR signal strength. Overall our data indicate that Gli3 expressed in the thymus stroma regulates negative selection and TCR signal strength via Hh-dependent and -independent mechanisms, with implications for autoimmunity.

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Section: Hytcrtggli3supporting

confidence: 81%

“…These signaling proteins are required for efficient maturation and differentiation of the earliest double negative (DN) populations (3,4,6,7,10,12). Shh also influences TCR repertoire selection, most likely by modulating TCR signal strength (11,29).…”

Section: The Gli3 Transcription Factor Expressed In the Thymusmentioning

confidence: 99%

The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms

Hager-Theodorides

Furmanski²,

Ross³

et al. 2009

The Journal of Immunology

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“…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%

“…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. 20,26 Therefore, to examine differentiation from DN to DP in a synchronized wave, we used treatment with hydrocortisone (HC) to deplete the adult thymus by inducing apoptosis in all but the most mature cells. 27 We then followed the recovery of the DP population, as the thymus grows to recover its normal size and subset distribution during the week after treatment.…”

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

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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Repression of Hedgehog signal transduction in T-lineage cells increases TCR-induced activation and proliferation

Cited by 37 publications

References 20 publications

The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms

The Gli3 Transcription Factor Expressed in the Thymus Stroma Controls Thymocyte Negative Selection Via Hedgehog-Dependent and -Independent Mechanisms

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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