Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis

Guo, Fukun; Hildeman, David A.; Tripathi, Pulak; Velu, Chinavenmeni S.; Grimes, H. Leighton; Zheng, Yi

doi:10.1073/pnas.1010249107

Cited by 54 publications

(74 citation statements)

References 51 publications

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“…So far, an autoregulatory role for Gfi1 as well as a transregulatory role for Gfi1b has been documented (53). Also, downstream signaling of the GTPase Cdc42 has been proposed to suppress Gfi1 expression in resting T cells (54). The current study now proposes that glucocorticoids are a new family of molecules that can control Gfi1 expression.…”

Section: Discussionmentioning

confidence: 71%

CD8 Lineage-specific Regulation of Interleukin-7 Receptor Expression by the Transcriptional Repressor Gfi1

Ligons

Tuncer

Linowes

et al. 2012

Journal of Biological Chemistry

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Background: Expression of the IL-7R␣ gene is up-/down-regulated during T/B-lymphocyte development. Results: IL-7R␣ gene transcription is repressed by the transcription factor Gfi1, specifically in CD8 ϩ T-lymphocytes. Conclusion:Treatment by dexamethasone down-regulates Gfi1, which contributes to glucocorticoid receptor mediated upregulation of IL-7R expression. Significance: The mechanism by which the IL-7R gene gets turned on and off during development is a critical issue in biology. Interleukin-7 receptor ␣ (IL-7R␣) is essential for T cell survival and differentiation. Glucocorticoids are potent enhancers of IL-7R␣ expression with diverse roles in T cell biology.Here we identify the transcriptional repressor, growth factor independent-1 (Gfi1), as a novel intermediary in glucocorticoid-induced IL-7R␣ up-regulation. We found Gfi1 to be a major inhibitory target of dexamethasone by microarray expression profiling of 3B4.15 T-hybridoma cells. Concordantly, retroviral transduction of Gfi1 significantly blunted IL-7R␣ up-regulation by dexamethasone. To further assess the role of Gfi1 in vivo, we generated bacterial artificial chromosome (BAC) transgenic mice, in which a modified Il7r locus expresses GFP to report Il7r gene transcription. By introducing this BAC reporter transgene into either Gfi1-deficient or Gfi1-transgenic mice, we document in vivo that IL-7R␣ transcription is up-regulated in the absence of Gfi1 and down-regulated when Gfi1 is overexpressed. Strikingly, the in vivo regulatory role of Gfi1 was specific for CD8 ؉ , and not CD4 ؉ T cells or immature thymocytes. These results identify Gfi1 as a specific transcriptional repressor of the Il7r gene in CD8 T lymphocytes in vivo.

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Section: Discussionmentioning

confidence: 71%

CD8 Lineage-specific Regulation of Interleukin-7 Receptor Expression by the Transcriptional Repressor Gfi1

Ligons

Tuncer

Linowes

et al. 2012

Journal of Biological Chemistry

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“…We tested the function of Cdc42 in Tregs because it had been previously shown that T cell-specific deletion of Cdc42 resulted in decreased T cell trafficking and cell survival (31). As expected, the number of Tregs was drastically decreased in lungs of Foxp3…”

Section: Creert2mentioning

confidence: 88%

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

Singh¹,

Eken²,

Hagin³

et al. 2017

JCI Insight

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“…20 As such, WASp is classically involved in actin rearrangement processes at the cell leading edge leading to membrane protrusions. WASp also controls podosome assembly and integrindependent adhesion, and is implicated in cell migration.…”

Section: Discussionmentioning

confidence: 99%

“…20 To determine WASp and PAK binding, National Institutes of Health (NIH) 3T3 cells overexpressing HA3-tagged-Cdc42S71P were subjected to the pull-down assay using the Cdc42 effector probe, GST-WASp or GST-PAK, as previously described. 20 MxCre Tg/ϩ ;WT and MxCre Tg/ϩ ; Cdc42 flox/flox bone marrow cells were transduced with retroviral supernatant. 10,21 EGFP ϩ cells were isolated and transplanted into lethally irradiated C57Bl/6 animals.…”

Section: Retroviral Transduction Of Mutant Vectorsmentioning

confidence: 99%

Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules

Kumar

Perkins

et al. 2012

Blood

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Chemotaxis promotes neutrophil participation in cellular defense by enabling neutrophil migration to infected tissue and is controlled by persistent cell polarization. One long-standing question of neutrophil polarity has been how the pseudopod and the uropod are coordinated. In our previous report, we suggested that Rho GTPase Cdc42 controls neutrophil polarity through CD11b signaling at the uropod, albeit through an unknown mechanism. Here, we show that Cdc42 controls polarity, unexpectedly, via its effector WASp. Cdc42 controls WASp activation and its distant localization to the uropod. At the uropod, WASp regulates the reorganization of CD11b integrin into detergent resistant membrane domains; in turn, CD11b recruits the microtubule end binding protein EB1 to capture and stabilize microtubules at the uropod. This organization is necessary to maintain neutrophil polarity during migration and is critical for neutrophil emigration into inflamed lungs. These results suggest unrecognized mechanism of neutrophil polarity in which WASp mediates long-distance control of the uropod by Cdc42 to maintain a proper balance between the pseudopod and the uropod. IntroductionNeutrophils are the most abundant leukocyte and fastest moving cell in the body. Neutrophils play a central role in innate immunity as cellular defense against infecting microorganisms and inflammatory processes and can contribute to hyperinflammatory reactions causing tissue injury. Neutrophils move rapidly toward sites of infection through a multiple-step process that involves tethering, rolling, adhesion, and transmigration to reach the site of infection in the tissue. Moreover, a new step in the neutrophil extravasation cascade, so-called locomotion, has been recently identified where neutrophils crawl onto endothelium toward the nearest endothelial junctions before transmigrating into tissues. [1][2][3] Failure to regulate any of these events of neutrophil extravasation may lead to abnormal innate immune responses, including immunodeficiency or aberrant inflammatory reactions. Therefore, understanding the molecular mechanisms that control neutrophil migration is of significant therapeutic importance.Neutrophils are one of the fastest migrating cells in response to a shallow chemoattractant gradient. Migrating neutrophils are highly polarized cells, which enables them to persistently migrate along the chemotactic gradient. During this process, filamentous actin (F-actin) polymerizes asymmetrically at the cell leading edge, and provides the protrusive forces to propel the cell membrane forward. At the same time, lateral membrane protrusions (so-called secondary/abnormal protrusions) are inhibited by actomyosin contractile complexes forming along the cell sides and the trailing edge, or uropod. [4][5][6] Members of the Rho GTPase family, including Rho, Rac, and Cdc42, are key regulators of chemotaxis. They cycle between an inactive, GDP-bound and active, GTP-bound forms via guanine nucleotide exchange factors (GEFs) and GTPaseactivating proteins (GAP...

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Coordination of IL-7 receptor and T-cell receptor signaling by cell-division cycle 42 in T-cell homeostasis

Cited by 54 publications

References 51 publications

CD8 Lineage-specific Regulation of Interleukin-7 Receptor Expression by the Transcriptional Repressor Gfi1

CD8 Lineage-specific Regulation of Interleukin-7 Receptor Expression by the Transcriptional Repressor Gfi1

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules

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