CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation

Kennedy, James; Fodil, Nassima; Torre, Sabrina; Bongfen, Silayuv E.; Olivier, Jean-Frédéric; Leung, Vicki; Langlais, David; Meunier, Charles; Berghout, Joanne; Langat, Pinky; Schwartzentruber, Jeremy; Majewski, Jacek; Lathrop, Mark; Vidal, Silvia M.; Gros, Philippe

doi:10.1084/jem.20140455

Cited by 46 publications

(87 citation statements)

References 66 publications

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“…Among the down-regulated genes, the only non-mitochondrial gene was CCDC88B, coding for coiled-coil domain containing protein 88b, that is expressed in lymphocytes and myeloid cells and may have a role in regulation of T-cell function during inflammation [64]. Interestingly, this gene showed an unusual behaviour in cells treated with different dilutions (Fig 5): its expression decreased in samples from cells treated with low dilutions of Arnica m .…”

Section: Discussionmentioning

confidence: 99%

Arnica montana Stimulates Extracellular Matrix Gene Expression in a Macrophage Cell Line Differentiated to Wound-Healing Phenotype

et al. 2016

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Arnica montana (Arnica m.) is used for its purported anti-inflammatory and tissue healing actions after trauma, bruises, or tissue injuries, but its cellular and molecular mechanisms are largely unknown. This work tested Arnica m. effects on gene expression using an in vitro model of macrophages polarized towards a “wound-healing” phenotype. The monocyte-macrophage human THP-1 cell line was cultured and differentiated with phorbol-myristate acetate and Interleukin-4, then exposed for 24h to Arnica m. centesimal (c) dilutions 2c, 3c, 5c, 9c, 15c or Control. Total RNA was isolated and cDNA libraries were sequenced with a NextSeq500 sequencer. Genes with significantly positive (up-regulated) or negative (down-regulated) fold changes were defined as differentially expressed genes (DEGs). A total of 20 DEGs were identified in Arnica m. 2c treated cells. Of these, 7 genes were up-regulated and 13 were down-regulated. The most significantly up-regulated function concerned 4 genes with a conserved site of epidermal growth factor-like region (p<0.001) and three genes of proteinaceous extracellular matrix, including heparin sulphate proteoglycan 2 (HSPG2), fibrillin 2 (FBN2), and fibronectin (FN1) (p<0.01). Protein assay confirmed a statistically significant increase of fibronectin production (p<0.05). The down-regulated transcripts derived from mitochondrial genes coding for some components of electron transport chain. The same groups of genes were also regulated by increasing dilutions of Arnica m. (3c, 5c, 9c, 15c), although with a lower effect size. We further tested the healing potential of Arnica m. 2c in a scratch model of wound closure based on the motility of bone marrow-derived macrophages and found evidence of an accelerating effect on cell migration in this system. The results of this work, taken together, provide new insights into the action of Arnica m. in tissue healing and repair, and identify extracellular matrix regulation by macrophages as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Arnica montana Stimulates Extracellular Matrix Gene Expression in a Macrophage Cell Line Differentiated to Wound-Healing Phenotype

et al. 2016

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“…In line with our hypothesis we found that CD4-Cre Mysm1 fl/fl mice show increased survival. 46 In this study, we have identified a novel role for chromatin-interacting deubiquitinase MYSM1 in CD8 + T-cell development and function. No major differences in the IFN-c or TNF-a production by CD4 + or CD8 + T cells from the CD4-Cre Mysm1 fl/fl ECM mice was detected, prompting us to conclude that the improved survival of CD4-Cre Mysm1 fl/fl mice is probably dependent on the reduction of CD8 + T-cell numbers.…”

Section: Discussionmentioning

confidence: 87%

A role for the histone H2A deubiquitinase MYSM1 in maintenance of CD8⁺ T cells

et al. 2017

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Several previous studies outlined the importance of the histone H2A deubiquitinase MYSM1 in the regulation of stem cell quiescence and haematopoiesis. In this study we investigated the role of MYSM1 in T-cell development. Using mouse models that allow conditional Mysm1 ablation at late stages of thymic development, we found that MYSM1 is intricately involved in the maintenance, activation and survival of CD8 T cells. Mysm1 ablation resulted in a twofold reduction in CD8 T-cell numbers, and also led to a hyperactivated CD8 T-cell state accompanied by impaired proliferation and increased pro-inflammatory cytokine production after ex vivo stimulation. These phenotypes coincided with an increased apoptosis and preferential up-regulation of p53 tumour suppressor protein in CD8 T cells. Lastly, we examined a model of experimental cerebral malaria, in which pathology is critically dependent on CD8 T cells. In the mice conditionally deleted for Mysm1 in the T-cell compartment, CD8 T-cell numbers remained reduced following infection, both in the periphery and in the brain, and the mice displayed improved survival after parasite challenge. Collectively, our data identify MYSM1 as a novel factor for CD8 T cells in the immune system, increasing our understanding of the role of histone H2A deubiquitinases in cytotoxic T-cell biology.

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“…While revising our manuscript, HkRP3 (CCDC88B) was identified as a gene responsible for pathological inflammation via a genome-wide screen of ENU ( N -ethyl- N -nitrosourea)-mutagenized mice (46). Loss of HkRP3 was found to induce resistance in an experimental cerebral malaria (ECM) model, which normally leads to severe inflammatory responses and lethality.…”

Section: Discussionmentioning

confidence: 99%

HkRP3 Is a Microtubule-Binding Protein Regulating Lytic Granule Clustering and NK Cell Killing

Ham

Huynh

Schoon

et al. 2015

The Journal of Immunology

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NK cells provide host defense by killing viral-infected and cancerous cells through the secretion of preformed lytic granules. Polarization of the lytic granules toward the target cell is dependent on an intact microtubule (MT) network as well as MT motors. We have recently shown that DOCK8, a gene mutated in a primary immunodeficiency syndrome, is involved in NK cell killing in part through its effects on MTOC polarization. In this study, we identified Hook-related protein 3 (HkRP3) as a novel DOCK8- and MT-binding protein. We further show that HkRP3 is present in lytic granule fractions, interacts with the dynein motor complex and MTs. Significantly, depletion of HkPR3 impaired NK cell cytotoxicity, which could be attributed to a defect in not only MTOC polarity, but also impaired clustering of lytic granules around the MTOC. Our results demonstrate an important role for HkRP3 in regulating the clustering of lytic granules and MTOC repositioning during the development of NK cell-mediated killing.

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CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation

Cited by 46 publications

References 66 publications

Arnica montana Stimulates Extracellular Matrix Gene Expression in a Macrophage Cell Line Differentiated to Wound-Healing Phenotype

Arnica montana Stimulates Extracellular Matrix Gene Expression in a Macrophage Cell Line Differentiated to Wound-Healing Phenotype

A role for the histone H2A deubiquitinase MYSM1 in maintenance of CD8⁺ T cells

HkRP3 Is a Microtubule-Binding Protein Regulating Lytic Granule Clustering and NK Cell Killing

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CCDC88B is a novel regulator of maturation and effector functions of T cells during pathological inflammation

Cited by 46 publications

References 66 publications

Arnica montana Stimulates Extracellular Matrix Gene Expression in a Macrophage Cell Line Differentiated to Wound-Healing Phenotype

Arnica montana Stimulates Extracellular Matrix Gene Expression in a Macrophage Cell Line Differentiated to Wound-Healing Phenotype

A role for the histone H2A deubiquitinase MYSM1 in maintenance of CD8+ T cells

HkRP3 Is a Microtubule-Binding Protein Regulating Lytic Granule Clustering and NK Cell Killing

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A role for the histone H2A deubiquitinase MYSM1 in maintenance of CD8⁺ T cells