Characterization of the thymic IL-7 niche in vivo

Alves, Nuno L.; Goff, Odile Richard-Le; Huntington, Nicholas D.; Sousa, Ana Patricia; Ribeiro, Vera S. G.; Bordack, Allison; Vives, Francina Langa; Peduto, Lucie; Chidgey, Ann Patricia; Cumano, Ana; Boyd, Richard; Eberl, Gérard; Santo, James P. Di

doi:10.1073/pnas.0809559106

Cited by 131 publications

(132 citation statements)

References 36 publications

(64 reference statements)

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“…Recent studies using IL-7 reporter mice revealed that, similar to the predominance of IL-17 + gd T cells in the thymus of young mice (8), the number of IL-7-expressing thymic epithelial cells was higher in neonatal and 1-2-wk-old mice than in adult mice (49). In addition to the thymus, IL-7-expressing cells were found in peripheral organs, such as abdomen, lung, skin, and intestine, where IL-17 + gd T cells were localized (50).…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

Nakamura

Shibata

Hatano

et al. 2015

The Journal of Immunology

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Notch signaling is an important regulator for the development and function of both αβ and γδ T cells, whereas roles of Notch signaling in T cell maintenance remain unclear. We reported previously that the Notch–Hes1 pathway was involved in the intrathymic development of naturally occurring IL-17–producing (IL-17+) γδ T cells. To gain insight into additional roles for the Notch axis in the homeostasis of γδ T cells, we performed a genome-wide analysis of Notch target genes and identified the novel promoter site of IL-7Rα driven by the Notch–RBP-Jκ pathway. Constitutive Notch signaling had the potential to induce IL-7Rα expression on γδ T cells in vivo, as well as in vitro, whereas conditional deletion of RBP-Jκ abrogated IL-7Rα expression, but not Hes1 expression, by γδ T cells and selectively reduced the pool size of IL-7Rαhigh IL-17+ γδ T cells in the periphery. In the absence of IL-7Rα–mediated signaling, IL-17+ γδ T cells were barely maintained in adult mice. Addition of exogenous IL-7 in vitro selectively expanded IL-17+ γδ T cells. Thus, our results revealed a novel role for the Notch–RBP-Jκ–IL-7Rα axis that is independent of Hes1 for homeostasis of IL-17+ γδ T cells.

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Section: Discussionmentioning

confidence: 99%

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

Nakamura

Shibata

Hatano

et al. 2015

The Journal of Immunology

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“…Like other related cytokines (IL-2, IL-4, IL-9, IL-15, and IL-21), IL-7 is a member of the so-called common g-chain (g c ) family (2). It is produced by many different stromal cell types, including epithelial cells of the thymus and the intestine (3)(4)(5). The receptor for IL-7 consists of a heterodimer, the IL7Ra-chain, and the g c ; the IL-7Ra-chain is also part of the receptor for the thymic stromal lymphopoietin (TSLP) cytokine, and g c is also a component of other cytokine receptors (2).…”

mentioning

confidence: 99%

Genetic Evidence for an Evolutionarily Conserved Role of IL-7 Signaling in T Cell Development of Zebrafish

Iwanami

Mateos

Hess

et al. 2011

The Journal of Immunology

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In mammals, the cytokine IL-7 is a key regulator of various aspects of lymphocyte differentiation and homeostasis. Because of the difficulty of identifying cytokine homologs in lower vertebrates and the paucity of assay systems and reagents, the degree of functional conservation of cytokine signaling pathways, particularly those pertaining to lymphocyte development, is unclear. In this article, we report on the analysis and characterization of three zebrafish mutants with severely impaired thymopoiesis. The identification of affected genes by positional cloning revealed components of the IL-7 signaling pathway. A presumptive null allele of the zebrafish homolog of the IL-7Rα–chain causes substantially reduced cellularity of the thymus but spares B cell development in the kidney. Likewise, nonsense mutations in the zebrafish homologs of janus kinases JAK1 and JAK3 preferentially affect T cell development. The functional interactions of the cytokine receptor components were examined in the three groups of fish hetero- or homozygous for either il7r and jak1, il7r and jak3, or jak1 and jak3 mutations. The differential effects on T cell development arising from the different genotypes could be explained on the basis of the known structure of the mammalian IL-7R complex. Because IL-7 signaling appears to be a universal requirement for T cell development in vertebrates, the mutants described in this article represent alternative animal models of human immunodeficiency syndromes amenable to large-scale genetic and chemical screens.

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“…Evidence suggests that trans-presentation of IL-15 by parenchymal cells is crucial in the development of IL-15 responsive cells such as invariant NKT cells in the thymus [23,24]. One could envisage the IL-15Ra 1 thymic stroma presenting IL-15 and working in synergy with locally expressed IL-7 [22] to promote immature thymocyte development and perhaps invariant NKT-cell development.…”

Section: Discussionmentioning

confidence: 99%

“…While IL-15 does not appear essential for thymopoiesis in mice [20,21], previous studies have shown that TEC subsets express IL-15 [22] and could ''trans-present'' IL-15/IL-15Ra complexes to developing thymocytes [23,24]. Since the bioavailability of human IL-15 in HIS mice appears limited [3], we next investigated the effect of exogenous IL-15 on human thymopoiesis in vivo.…”

Section: Effects Of Exogenous Human Il-15 Administration On Human Thymentioning

confidence: 99%

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Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

et al. 2011

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PortugalHuman Immune System (HIS) mice represent a novel biotechnology platform to dissect human haematopoiesis and immune responses. However, the limited human T-cell development that is observed in HIS mice restricts its utility for these applications. Here, we address whether reduced thymopoiesis in HIS mice reflects an autonomous defect in T-cell precursors and/or a defect in the murine thymic niche. Human thymocyte precursors seed the mouse thymus and their reciprocal interactions with murine thymic epithelial cells (TECs) led to both T-cell and TEC maturation. The human thymocyte subsets observed in HIS mice demonstrated survival, proliferative and phenotypic characteristics of their normal human counterparts, suggesting that the intrinsic developmental program of human thymocytes unfolds normally in this xenograft setting. We observed that exogenous administration of human IL-15/IL-15Ra agonistic complexes induced the survival, proliferation and absolute numbers of immature human thymocyte subsets, without any obvious effect on cell-surface phenotype or TCR Vb usage amongst the newly selected mature singlepositive (SP) thymocytes. Finally, when IL-15 was administered early after stem cell transplantation, we noted accelerated thymopoiesis resulting in the more rapid appearance of peripheral naïve T cells. Our results highlight the functional capacity of murine thymic stroma cells in promoting human thymopoiesis in HIS mice but suggest that the ''cross-talk'' between murine thymic stroma and human haematopoietic precursors may be suboptimal. As IL-15 immunotherapy promotes early thymopoiesis, this novel approach could be used to reduce the period of T-cell immunodeficiency in the post-transplant clinical setting. IntroductionSixty million years of evolution has generated important differences between the murine and human immune systems (HISs). As such, our knowledge of lymphocyte development, homeostasis and immune responses that is largely derived from mouse studies may not be directly applicable to man. The recent advances in the development of HIS mice provide a new model to experimentally dissect human lymphocyte biology that may eventually allow us to bridge the knowledge gap between murine and human in vivo studies of immune responses. T-cell development depends on instructive temporal-spatial signals provided by a resident cellular network known as thymic stroma [6,7]. TECs represent the main thymic stromal compartment in the pre-involution thymus and constitute a multifunctional platform that supports thymocyte commitment, survival, division, migration and selection. TECs are classically divided into two specialized functional subsets, cortical (cTECs) and medullary (mTECs). While cTECs are important at early stages of T-cell development and mediate positive selection, mTECs are critical at later stages governing negative selection and providing survival signals to mature single-positive (SP) thymocytes [6,8,9]. The generation of these two functionally competent TEC compartments is a prerequisite ...

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Characterization of the thymic IL-7 niche in vivo

Cited by 131 publications

References 36 publications

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

Genetic Evidence for an Evolutionarily Conserved Role of IL-7 Signaling in T Cell Development of Zebrafish

Autonomous and extrinsic regulation of thymopoiesis inhuman immune system (HIS) mice

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