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

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

doi:10.4049/jimmunol.0900152

Cited by 36 publications

(52 citation statements)

References 58 publications

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“…It may also differ from the function of other components involved in canonical Hh signaling. Examples are Hh, which was reported to activate or inhibit intrathymic T cell proliferation and differentiation in a dose-dependent manner (2,3), and Gli2 and Gli3, which were shown to influence, for example, TCR repertoire selection (8,9).…”

Section: Discussionmentioning

confidence: 99%

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T Cell Development Critically Depends on Prethymic Stromal Patched Expression

Uhmann

Brandt

Dittmann

et al. 2011

The Journal of Immunology

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We recently described that T cell specification in mice deficient in the Hedgehog (Hh) receptor Patched (Ptch) is blocked at the level of the common lymphoid progenitor in the bone marrow (BM). Adoptive transfer of wild-type BM in Ptch-deficient mice provides evidence that T cell development strictly depends on Ptch expression in the nonhematopoietic compartment. Transplantation experiments using BM deficient in the glucocorticoid receptor exclude any involvement of the stress hormone corticosterone in our model. Using cell-type–specific knockout mice, we show that T cell development is independent of T cell-intrinsic Ptch expression. Furthermore, Ptch expression by the thymus stroma is dispensable, as revealed by fetal thymus organ culture and thymus transplantation. In contrast, analysis of the earliest thymic progenitors in Ptch-deficient mice indicated that Ptch is required for the development or supply of thymic homing progenitors that give rise to earliest thymic progenitors. Collectively, our findings identified Ptch as an exclusive T cell-extrinsic factor necessary for proper development of T cells at their prethymic stage. This observation may be important for current considerations using Hh inhibitors upstream of Ptch in diseases accompanied by aberrant Hh signaling.

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Section: Discussionmentioning

confidence: 99%

“…Recently, it was shown that all major components of the Hhsignaling cascade (e.g., Hh, Ptch, Smo, and Gli) are important for T cell development (2)(3)(4)(5)(6)(7)(8)(9). In the thymus, Hh is produced by the thymic stroma, where Ptch and its signaling partner Smo are expressed (2,6).…”

mentioning

confidence: 99%

T Cell Development Critically Depends on Prethymic Stromal Patched Expression

Uhmann

Brandt

Dittmann

et al. 2011

The Journal of Immunology

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“…Transcription factors, such as Th-POK, play essential roles in lineage commitment, and the ways in which the transcriptional regulation of lineage commitment relate to TCR signaling require further study [11]. In addition, other secreted factors from TEC, such as the morphogen Sonic hedgehog influence TCR repertoire selection and differentiation from DP to SP cell [13,14].…”

Section: A Very Brief Overview Of T Cell Developmentmentioning

confidence: 99%

CD3+CD4−CD8− (double negative) T cells: Saviours or villains of the immune response?

D’Acquisto¹,

Crompton²

2011

Biochemical Pharmacology

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158

132

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To cite this version:Fulvio D'Acquisto, Tessa Crompton. CD3CD4CD8 (double negative) T cells: saviours or villains of the immune response?. Biochemical Pharmacology, Elsevier, 2011, 82 (4) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 29A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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“…Knockout (KO) and transgenic mouse models show that Hh signaling regulates thymocyte development (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). Peripheral T cells express components of the Hh signaling pathway (15), which is involved in regulation of T cell activation in vitro (11,12,15,16).…”

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confidence: 99%

Tissue-Derived Hedgehog Proteins Modulate Th Differentiation and Disease

Furmanski

Saldaña

Ono

et al. 2013

The Journal of Immunology

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120

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Genome-wide association studies into complex immune-mediated diseases have indicated that many genetic factors, each with individual low risk, contribute to overall disease. It is therefore timely and important to characterise how immune responses may be subtly modified by tissue context. Here we explore the role of tissue-derived molecules in influencing the function of T-cells, which, due to their migratory nature, come into contact with many different microenvironments through their lifespan. Hedgehog (Hh) proteins act as secreted morphogens, providing concentration-dependent positional and temporal cell-fate specification in solid tissues. Hh signalling is required for embryogenesis and is important in postnatal tissue renewal and in malignancy. However, the function of Hh in dynamic, fluid systems such as in mammalian immunity is largely unknown. Here we show that Hh-dependent transcription in T-cells promoted Th2 transcriptional programs and differentiation, exacerbating allergic pathology. Interestingly, expression of Sonic Hedgehog (Shh) increased in lung epithelial cells following the induction of allergic disease, and lung T-cells upregulated Hh-target gene expression, indicating that T-cells respond to locally-secreted Hh ligands in vivo. We show that Il4, the key Th2 cytokine, is a novel transcriptional target of Hh signals in T-cells, providing one mechanism for the role of Hh in Th differentiation. We propose that Hh, secreted from inflamed, remodelling or malignant tissue can modulate local T-cell function. Our data present an unexpected and novel role for tissue-derived morphogens in the regulation of fluid immune responses, with implications for allergy and tumour responses, suggesting new uses for anti-Hh therapeutics.

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

Cited by 36 publications

References 58 publications

T Cell Development Critically Depends on Prethymic Stromal Patched Expression

T Cell Development Critically Depends on Prethymic Stromal Patched Expression

CD3+CD4−CD8− (double negative) T cells: Saviours or villains of the immune response?

Tissue-Derived Hedgehog Proteins Modulate Th Differentiation and Disease

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