Stability and function of regulatory T cells is maintained by a neuropilin-1–semaphorin-4a axis

Delgoffe, Greg M.; Woo, Seng-Ryong; Turnis, Meghan E.; Gravano, David M.; Guy, Cliff; Overacre, Abigail E.; Bettini, Matthew L.; Vogel, Peter; Finkelstein, David; Bonnevier, Jody; Workman, Creg J.; Vignali, Dario A.A.

doi:10.1038/nature12428

Cited by 485 publications

(524 citation statements)

References 31 publications

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“…Dampened AKT activity in T Reg cells supports the expression of IL-2 receptor α-chain (IL-2Rα; also known as CD25) and the nuclear localization of forkhead box O (FOXO) transcription factors, both of which are crucial for preventing T Reg cell plasticity towards inflammatory programmes [79][80][81] . Additionally, neuropilin 1, a receptor that is highly expressed by mouse tT Reg cells, recruits PTEN to the immunological synapse and blocks the activation of AKT during TCR stimulation, thus promoting T Reg cell stability and function 82 . plasticity is depicted at three levels in the cell: extracellular cues (red), cytosolic signalling and metabolic programmes (orange) and transcription factor (TF)-or chromatin-mediated gene regulation (blue).…”

Section: Box 2 | Phenotypic Plasticity In Inflammatory and Regulatorymentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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| CD4 + T cells differentiate and acquire distinct functions to combat specific pathogens but can also adapt their functions in response to changing circumstances. Although this phenotypic plasticity can be potentially deleterious, driving immune pathology, it also provides important benefits that have led to its evolutionary preservation. Here, we review CD4 + T cell plasticity by examining the molecular mechanisms that regulate it -from the extracellular cues that initiate and drive cells towards varying phenotypes, to the cytosolic signalling cascades that decipher these cues and transmit them into the cell and to the nucleus, where these signals imprint specific gene expression programmes. By understanding how this functional flexibility is achieved, we may open doors to new therapeutic approaches that harness this property of T cells.

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Section: Box 2 | Phenotypic Plasticity In Inflammatory and Regulatorymentioning

confidence: 99%

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

2016

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“…6 A and B). This category also includes genes that only recently have been shown to be of importance, such as neuropilin 1 (Nrp1) (ranked sixth out of 22,399 genes) (35) and Itgb8 (ranked 13th). The use of Itgb8 as a marker for thymically derived Tregs and its importance in Treg-mediated immunosuppression was verified experimentally and reported during the preparation of this paper (36,37).…”

Section: Analysis Of Expression Correlation Of Treg-specific Genes Rementioning

confidence: 99%

Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system

Vandenbon

Dinh

Mikami

et al. 2016

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

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High-throughput gene expression data are one of the primary resources for exploring complex intracellular dynamics in modern biology. The integration of large amounts of public data may allow us to examine general dynamical relationships between regulators and target genes. However, obstacles for such analyses are studyspecific biases or batch effects in the original data. Here we present Immuno-Navigator, a batch-corrected gene expression and coexpression database for 24 cell types of the mouse immune system. We systematically removed batch effects from the underlying gene expression data and showed that this removal considerably improved the consistency between inferred correlations and prior knowledge. The data revealed widespread cell type-specific correlation of expression. Integrated analysis tools allow users to use this correlation of expression for the generation of hypotheses about biological networks and candidate regulators in specific cell types. We show several applications of Immuno-Navigator as examples. In one application we successfully predicted known regulators of importance in naturally occurring Treg cells from their expression correlation with a set of Treg-specific genes. For one high-scoring gene, integrin β8 (Itgb8), we confirmed an association between Itgb8 expression in forkhead box P3 (Foxp3)-positive T cells and Treg-specific epigenetic remodeling. Our results also suggest that the regulation of Tregspecific genes within Treg cells is relatively independent of Foxp3 expression, supporting recent results pointing to a Foxp3-independent component in the development of Treg cells.

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“…Current efforts are underway by Maria Grazia Roncarolo et al to translate these finding to clinical applications in bone marrow and kidney transplantation [10]. Lastly, a unique subset of suppressive T cells has been identified in mice, iT R 35, which does not require any of the hallmarks of other suppressor T cells including forkhead box 3 (FoxP3), IL-10 or TGF-b to suppress but rather uses a novel cytokine, IL-35, to shut down effector T cell function directly through a Neuropilin-1/Semaphorin A pathway, and data by Vignali et al suggest it may be translatable in human [11,12]. All the suppressive T cell subsets described above are likely to be involved in immune homeostasis and tolerance with potential therapeutic application; however, these cell subtypes are not critical to fundamental immune tolerance as their disruption does not lead to massive autoimmunity.…”

Section: Suppressive T Cell Populations Controlling Autoimmunitymentioning

confidence: 99%