Integrin αvβ8-Mediated TGF-β Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation

Worthington, John J.; Kelly, Aoife; Smedley, Catherine; Bauché, David; Campbell, Simon; Marie, Julien C.; Travis, Mark A.

doi:10.1016/j.immuni.2015.04.012

Cited by 155 publications

(170 citation statements)

References 44 publications

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“…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). Furthermore, top-scoring genes include multiple genes that have been reported by other studies as having high expression in Tregs, including Mdfic (ranked 17th), Prnp (ranked 28th; see also ref.…”

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

confidence: 56%

“…7C). Recent studies showed that Itgb8 expression by Treg cells plays a role in controlling the release of active TGB-β1 and in suppressing inflammation (36,37). Although the underlying molecular mechanism remains unclear, our result suggests that Itgb8-expressing Treg cells might represent functionally stable Treg cells.…”

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

confidence: 56%

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

confidence: 56%

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

confidence: 56%

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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“…In this way, the intestinal microenvironment promotes DCs to ‘recapitulate’ the same environment in the MLN during T cell presentation, which we propose allows fine spatio-temporal regulation of TGF-β signaling and thus induction of appropriate mucosal responses and homing in T cells. In addition, it has recently been shown that αvβ8 is expressed by Tregs, and contributes to ongoing immune regulation (63); whether β8 expression is also activated by RA and TGF-β in T cells remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

β8 Integrin Expression and Activation of TGF-β by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage

Boucard-Jourdin

Kugler²,

Ahanda

et al. 2016

The Journal of Immunology

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Activation of TGF-β by dendritic cells (DCs) expressing αvβ8 integrin is essential for the generation of intestinal regulatory T cells (Tregs) that in turn promote tolerance to intestinal antigens. We have recently shown that αvβ8 integrin is preferentially expressed by CD103+ DCs, and confers their ability to activate TGF-β and generate Tregs. However, how these DCs become specialized for this vital function is unknown. Here we show that β8 expression is controlled by a combination of factors that include DC lineage, and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-β itself, along with retinoic acid (RA) and Toll-like receptor (TLR) signaling, drive expression of αvβ8 in DCs. However, these signals only result in high levels of β8 expression in cells of the cDC1 lineage, CD8α+ or CD103+CD11b− DCs, and this is associated with epigenetic changes in the Itgb8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory αvβ8-expressing DCs specialized for activation of TGF-β to facilitate Treg generation.

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“…Cada una de las isoformas es sintetizada como un precursor que incluye: un péptido señal, un gran fragmento N-terminal llamado el péptido asociado a latencia (latency-associated peptide, en inglés LAP) y un pequeño fragmento C-terminal que es la citocina propiamente dicha (Travis and Sheppard, 2014). Existen múltiples mecanismos (el sistema de la trombospondina, varias integrinas, etc) para retirar el LAP, lo cual hace que la citocina cobre actividad y que permiten regular su función de una forma diferencial y específica de órgano (Travis and Sheppard, 2014;Worthington, et al, 2015).…”

Section: El Tgf-β En La Respuesta Inmuneunclassified

Papel del TGF-β en la inmunidad contra los rotavirus

Franco-Cortés

2016

Rev. Acad. Colomb. Cienc. Ex. Fis. Nat.

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ResumenLa vía de entrada y el principal sitio de replicación de los rotavirus es el intestino delgado. En este órgano el TGF-β juega un papel muy importante para mantener la tolerancia a los alimentos y microorganismos comensales. Por esta razon, es probable que esta citocina juegue un papel modulador en esta infección. Experimentos in vitro de nuestro laboratorio han mostrado que células humanas epiteliales infectadas por rotavirus aumentan la secreción de TGF-β y promueven una baja respuesta de linfocitos T, la que es necesaria para la inmunidad antiviral. En este artículo de revisión se analiza en forma crítica la hipótesis que los rotavirus inducen la producción de TGF-β como mecanismo de evasión inmune.Palabras clave: rotavirus, inmunidad intestinal, factor de crecimiento transformante Beta, tolerancia inmunológica, evasión inmunológica de virus. Role of TGF-β in rotavirus immunity AbstractRotavirus enter their host and predominantly replicates in the small intestine. In this organ, TGF-β plays an important role in maintaining tolerance to commensal microorganisms and food. For this reason, it is probable that this citokine plays a role in modulating viral infection. Results from our laboratory have shown that in vitro human cells infected with rotavirus secrete increased levels of TGF-β and promote an attenuated T cell response, which is necessary for protective cellular immunity. In this review article, I will critically evaluate the hypothesis that rotavirus induce the production of TGF-β as an immune evasion mechanism.Key words: Rotavirus, intestinal immunity, transforming growth factor beta, immunological tolerance, viral immune evasion. Correspondencia:Manuel Antonio Franco-Cortés, mafranco@javeriana.edu.co Recibido: 25 de octubre de 2015 Aceptado: 15 de febrero de 2016 doi: http://dx.doi.org/10.18257/raccefyn.300 Ciencias biomédicas IntroducciónEl desarrollo de vacunas contra los rotavirus es un importante logro de la medicina moderna (Angel, et al., 2014). Sin embargo, las vacunas actualmente en uso son relativamente poco eficientes en los países en vías de desarrollo, donde son más útiles, y es importante entender mejor la inmunidad antiviral para mejorarlas (Angel, et al., 2014). La inmunidad que inducen los rotavirus no es esterilizante y en muchos casos es de corta duración (Angel, et al., 2012; Franco, et al., 2006). Es probable que durante el desarrollo de la respuesta inmune contra estos virus entren en juego mecanismos que favorecen una respuesta protectora, elementos reguladores negativos de la respuesta inmune y, por último, las estrategias que ha desarrollado el virus para escapar a ésta (Angel, et al., 2012). El sistema inmune cuenta, entre otros, con 3 poderosos reguladores negativos: La proteína "muerte programada 1" (PD-1), la interleucina 10 (IL-10) y el factor de crecimiento transformante beta (TGF-β) (Freeman, et al., 2014; Garidou, et al., 2012). Dado que la principal puerta de entrada y sitio de replicación de los rotavirus es el intestino delgado, donde el TGF-β juega un papel ...

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Integrin αvβ8-Mediated TGF-β Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation

Cited by 155 publications

References 44 publications

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

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

β8 Integrin Expression and Activation of TGF-β by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage

Papel del TGF-β en la inmunidad contra los rotavirus

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