High levels of IL-7 cause dysregulation of thymocyte development

El-Kassar, Nahed; Flomerfelt, Francis A.; Choudhury, Baishakhi; Hugar, Lee A.; Chua, Kevin S.; Kapoor, Veena; Lucas, Paul A.; Gress, Ronald E.

doi:10.1093/intimm/dxs067

Cited by 21 publications

(16 citation statements)

References 40 publications

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“…Therefore, we suggest that suppression of B-cell development in thymus requires adequate IL-7 concentrations in addition to T-cell specification via Notch signaling. This is in agreement with a recent report that overexpression of IL-7 promotes extensive B-cell development in the thymus (36). TSLP concentrations might also contribute to this mechanism.…”

Section: Cd4sp Excluding Foxp3supporting

confidence: 93%

Interleukin-7 receptor controls development and maturation of late stages of thymocyte subpopulations

Tani-ichi

Shimba

Wagatsuma

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Interleukin (IL)-7 is a cytokine essential for T lymphocyte development and homeostasis. However, little is known about the roles of IL-7 receptor α-chain (IL-7Rα) in late stages of T-cell development. To address this question, we established IL-7Rα-floxed mice and crossed them with CD4-Cre transgenic mice. Resultant IL-7R conditional knockout (IL-7RcKO) mice exhibited marked reduction in CD8 single positive (SP) T cells, regulatory T cells (Tregs), and natural killer T (NKT) cells in thymus. The proportion and proliferation of both mature CD4SP and CD8SP thymocytes were decreased without affecting Runx expression. In addition, expression of the glucocorticoid-induced TNF receptor was reduced in CD4SP and CD8SP thymocytes, and expression of CD5 was decreased in CD8SP thymocytes. IL-7RcKO mice also showed impaired Treg and NKT cell proliferation and inhibition of NKT cell maturation. Bcl-2 expression was reduced in CD4SP and CD8SP thymocytes but not in Tregs and NKT cells, and introduction of a Bcl-2 transgene rescued frequency and CD5 expression of CD8SP thymocytes. Furthermore, IL-7RcKO mice exhibited greatly increased numbers of B cells and, to a lesser extent, γδ T and dendritic cells in thymus. Overall, this study demonstrates that IL-7Rα differentially controls development and maturation of thymocyte subpopulations in late developmental stages and suggests that IL-7R expression on αβ T cells suppresses development of other cell lineages in thymus.differentiation | survival

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Section: Cd4sp Excluding Foxp3supporting

confidence: 93%

Interleukin-7 receptor controls development and maturation of late stages of thymocyte subpopulations

Tani-ichi

Shimba

Wagatsuma

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…These results show the ETP population is highly sensitive to either up‐ or downregulation of IL‐7 signaling. High levels of IL‐7 have been shown to decrease ETP number 37 ; however, increased IL‐7 has a non‐linear effect on thymocyte development. Relatively low overexpression of IL‐7 increases thymocyte number while high levels result in an overall reduction in thymocyte numbers 38 .…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐7 in the transition of bone marrow progenitors to the thymus

et al. 2017

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Interleukin-7 (IL-7) is essential for the development of T cells in humans and mice where deficiencies in IL-7 signaling result in severe immunodeficiency. T cells require IL-7 at multiple points during development; however, it is unclear when IL-7 is first necessary. We observed that mice with impaired IL-7 signaling had a large reduction in the number of early thymic progenitors (ETPs) while mice that overexpress IL-7 had greatly increased numbers of ETPs. These results indicated that the development of ETPs is sensitive to IL-7. Bone marrow progenitors of ETP are present in normal numbers in mice with impaired IL-7 signaling (IL-7Rα) and were efficiently recruited to the thymus. Furthermore, ETPs and their progenitors from IL-7Rα mice did not undergo increased apoptosis and proliferate normally compared to WT cells. Mixed bone marrow chimeras demonstrated that IL-7 signaling has a cell-intrinsic role in ETP development but was not required for development of bone marrow progenitors. We have shown a novel role for IL-7 signaling in the development of ETPs that is distinct from classic mechanisms of IL-7 regulating survival and proliferation.

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“…The thymus can be a very favorable site for B‐cell development except where cells can receive Notch signals by direct contact with Notch ligands: Notch1 −/− precursors generate B cells abundantly in the thymus . Thus, when B‐cell potential is blocked early in mammalian T‐cell precursors , it is tempting to speculate that this is not only to maintain lineage fidelity but also to make sure T‐cell precursors do not need to compete for the local supply of IL‐7 . Imposing this block intrinsically is seen to be one of the earliest events in T‐cell development, and it is mediated at least in part by the Notch‐dependent induction of GATA‐3 which then maintains B‐lineage exclusion even when Notch signals are withdrawn .…”

Section: Hematopoiesis: a Distinctive Terrain For Gene Networkmentioning

confidence: 99%

Hematopoiesis and T‐cell specification as a model developmental system

Rothenberg

Kueh

Yui

et al. 2016

Immunological Reviews

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SUMMARY The pathway to generate T cells from hematopoietic stem cells guides progenitors through a succession of fate choices while balancing differentiation progression against proliferation, stage to stage. Many elements of the regulatory system that controls this process are known, but the requirement for multiple, functionally distinct transcription factors needs clarification in terms of gene network architecture. Here we compare the features of the T-cell specification system with the rule sets underlying two other influential types of gene network models: first, the combinatorial, hierarchical regulatory systems that generate the orderly, synchronized increases in complexity in most invertebrate embryos; second, the dueling “master regulator” systems that are commonly used to explain bistability in microbial systems and in many fate choices in terminal differentiation. The T-cell specification process shares certain features with each of these prevalent models but differs from both of them in central respects. The T-cell system is highly combinatorial but also highly dose-sensitive in its use of crucial regulatory factors. The roles of these factors are not always T-lineage specific, but they balance and modulate each other’s activities long before any mutually exclusive silencing occurs. T-cell specification may provide a new hybrid model for gene networks in vertebrate developmental systems.

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High levels of IL-7 cause dysregulation of thymocyte development

Cited by 21 publications

References 40 publications

Interleukin-7 receptor controls development and maturation of late stages of thymocyte subpopulations

Interleukin-7 receptor controls development and maturation of late stages of thymocyte subpopulations

Interleukin‐7 in the transition of bone marrow progenitors to the thymus

Hematopoiesis and T‐cell specification as a model developmental system

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