IFN-α Is Constitutively Expressed in the Human Thymus, but Not in Peripheral Lymphoid Organs

Colantonio, Arnaud D.; Epeldegui, Marta; Jesiak, Maria; Jachimowski, Loes C. M.; Blom, Bianca; Uíttenbogaart, Christel H.

doi:10.1371/journal.pone.0024252

Cited by 38 publications

(41 citation statements)

References 52 publications

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“…Indeed, factors such as TGFβ, Wnt, and type I interferons can all modify the maximum amplitude of Notch signaling through various ways (64) (Amsen, unpublished data). TECs produce TGFβ (71), while thymic plasmacytoid DCs constitutively express IFNα under non-inflamed conditions (72), indicating once more that both epithelial and non-epithelial stromal components of the thymic microenvironment might contribute to specialized niches capable of eliciting strong Notch signals in developing thymocytes. Given that mice lacking thymic epithelial cells still generate ILC2 (23), it is tempting to speculate that the relevant source of the Notch activating signals consists of a non-epithelial stromal cell.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Signal Strength Switches Notch from an Inducer of T Cells to an Inducer of ILC2

et al. 2013

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Innate lymphoid cells (ILCs) are emerging key players of the immune system with close lineage relationship to T cells. ILC2 play an important role in protective immunity against multicellular parasites, but are also involved in the pathogenesis of type 2 immune diseases. Here, we have studied the developmental requirements for human ILC2. We report that ILC2 are present in the thymus of young human donors, possibly reflecting local differentiation. Furthermore, we show that uncommitted lineage−CD34+CD1a−human thymic progenitors have the capacity to develop into ILC2 in vitro under the influence of Notch signaling, either by stimulation with the Notch ligand Delta like 1 (Dll1) or by expression of the active intracellular domain of NOTCH1 (NICD1). The capacity of NICD1 to mobilize the ILC2 differentiation program was sufficiently potent to override commitment to the T cell lineage in CD34+CD1a+ progenitors and force them into the ILC2 lineage. As Notch is an important factor also for T cell development, these results raise the question how one and the same signaling pathway can elicit such distinct developmental outcomes from the same precursors. We provide evidence that Notch signal strength is a critical determinant in this decision: by tuning signal amplitude, Notch can be converted from a T cell inducer (low signal strength) to an ILC2 inducer (high signal strength). Thus, this study enhances our understanding of human ILC2 development and identifies a mechanism determining specificity of Notch signal output during T cell and ILC2 differentiation.

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Section: Discussionmentioning

confidence: 99%

Modulation of Signal Strength Switches Notch from an Inducer of T Cells to an Inducer of ILC2

et al. 2013

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“…The activation of the innate immune system by poly(I:C) injection causes rapid ATI that is mediated by the virus-sensing melanoma differentiationassociated gene 5 receptor, and the type 1 IFN receptor significantly impacts this process (Anz et al 2009). Although IFN-α is constitutively present in the human thymus (Colantonio et al 2011) and acts as a key regulator of pathogeninduced ATI, microRNA miR-29a has also been found to play a critical role in the protection of thymus from involution. For instance, selective deletion of microRNA miR29a from the TECs leads to increased expression of the IFN-α receptor, which results in a loss of cellularity in the thymus and thus causes the ATI (Fig.…”

Section: Role Of Microrna and Ifn-α Receptors In Viral Infection Medimentioning

confidence: 99%

Acute Thymic Involution and Mechanisms for Recovery

Ansari

Liu

2017

Arch. Immunol. Ther. Exp.

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“…Previously, we have shown that human thymic pDCs are the likely source of the constitutive production of IFN‐α in the thymus as a result of TLR‐induced activation . Here we aimed at extending our findings.…”

Section: Resultsmentioning

confidence: 56%

“…1. We have previously shown that the amount of IFN‐α produced by thymic pDCs constitutively, or after stimulation with CpG or HIV, greatly varies between donors . Further, as shown in Fig.…”

Section: Resultsmentioning

confidence: 68%

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BST2/Tetherin is constitutively expressed on human thymocytes with the phenotype and function of Treg cells

2014

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In contrast to peripheral plasmacytoid dendritic cells (pDC), thymic pDC constitutively express low levels of IFN-α. This leads to induction of ISG in medullary thymocytes, raising the question whether IFN-α may play a role in T cell development. When characterizing further differences between peripheral and thymic pDC, we found that thymic pDC have a phenotype consistent with an “activated signature” including expression of TNF-α and BST2, but no expression of ILT7. Given that BST2 is induced by IFN-α and IFN-α secretion is controlled by interaction between ILT7 and BST2, this regulatory pathway is apparently lost in thymic pDC. Further, we also show that BST2 is expressed constitutively on a subset of medullary thymocytes at the mRNA and protein level reflecting a history of IFN-α transduced signals. The majority of BST2+ thymocytes express CCR5 rendering them prevalent targets for R5-tropic HIV infection. Moreover, BST2+ thymocytes express Foxp3 and CD25, consistent with the phenotype of natural Treg cells, and exert suppressive activity as they impair the proliferation of autologous CD3+ thymocytes. Collectively, our results suggest that low levels of IFN-α secreted by thymic pDC play an important role in the development of natural Treg cells.

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IFN-α Is Constitutively Expressed in the Human Thymus, but Not in Peripheral Lymphoid Organs

Cited by 38 publications

References 52 publications

Modulation of Signal Strength Switches Notch from an Inducer of T Cells to an Inducer of ILC2

Modulation of Signal Strength Switches Notch from an Inducer of T Cells to an Inducer of ILC2

Acute Thymic Involution and Mechanisms for Recovery

BST2/Tetherin is constitutively expressed on human thymocytes with the phenotype and function of Treg cells

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