WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts

Malinova, Dessislava; Fritzsche, Marco; Nowosad, Carla R.; Armer, Hannah; Munro, Peter; Blundell, Michael P.; Charras, Guillaume; Tolar, Pavel; Bouma, Gerben; Thrasher, Adrian J.

doi:10.1189/jlb.2a0215-050rr

Cited by 56 publications

(58 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These include cell secretion53, phagocytosis5455, autophagy56, migration5758, haptotaxis59, focal adhesions60 and intracellular tight junctions required for epidermal barrier formation61, vesicle trafficking and transcytosis in the small intestine62. With regards to immunity and inflammation, Arp2/3 function has been reported to be critical for the formation of immune cell synapses6364 and T-regulatory cell function, which is aberrant in WAS patients leading to a high susceptibility to develop Th2-mediated food allergies65. Genetic correction of induced pluripotential stem cells from WAS patients demonstrated the restoration of defective natural killer and T-lymphoid cell development and function, confirming the critical role of WASP66.…”

Section: Discussionmentioning

confidence: 99%

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

et al. 2017

View full text Add to dashboard Cite

Human actin-related protein 2/3 complex (Arp2/3), required for actin filament branching, has two ARPC1 component isoforms, with ARPC1B prominently expressed in blood cells. Here we show in a child with microthrombocytopenia, eosinophilia and inflammatory disease, a homozygous frameshift mutation in ARPC1B (p.Val91Trpfs*30). Platelet lysates reveal no ARPC1B protein and greatly reduced Arp2/3 complex. Missense ARPC1B mutations are identified in an unrelated patient with similar symptoms and ARPC1B deficiency. ARPC1B-deficient platelets are microthrombocytes similar to those seen in Wiskott–Aldrich syndrome that show aberrant spreading consistent with loss of Arp2/3 function. Knockout of ARPC1B in megakaryocytic cells results in decreased proplatelet formation, and as observed in platelets from patients, increased ARPC1A expression. Thus loss of ARPC1B produces a unique set of platelet abnormalities, and is associated with haematopoietic/immune symptoms affecting cell lineages where this isoform predominates. In agreement with recent experimental studies, our findings suggest that ARPC1 isoforms are not functionally interchangeable.

show abstract

Section: Discussionmentioning

confidence: 99%

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

et al. 2017

View full text Add to dashboard Cite

show abstract

“…WASp-deficient B lymphocytes are impaired in their ability to migrate, adhere, and form long protrusions [30]. In immature, WASpdeficient dendritic cells, podosomes are absent, residual dysmorphic lamellipodia and filopodia are not polarized, and migration is severely compromised [31,32]. Furthermore, T cells from WAS patients contain few, small surface microvilli and respond poorly to stroma cell-derived factor-1 (SDF-1) in migration assays [33] and to antigen receptorinduced stimulation [34].…”

Section: Wiskott-aldrich Syndromementioning

confidence: 99%

“…Furthermore, T cells from WAS patients contain few, small surface microvilli and respond poorly to stroma cell-derived factor-1 (SDF-1) in migration assays [33] and to antigen receptorinduced stimulation [34]. Taken as a whole, the data suggest that a defect in cell migration and membrane motility is the common denominator in this complex immunodeficiency [32]. The alteration of B cell homeostasis concerns both the central and peripheral compartments, and it has recently been described in detail [35].…”

Section: Wiskott-aldrich Syndromementioning

confidence: 99%

Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View

Cavazzana

Ribeil

Lagresle-Peyrou

et al. 2017

Stem Cells and Development

View full text Add to dashboard Cite

When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells (HSCs), there are only two in which the HSC and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject: metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD). In all other settings [X-linked severe combined immunodeficiency (X-SCID), adenosine deaminase deficiency, Wiskott-Aldrich syndrome, and b-hemoglobinopathies], the bone marrow content of the different stem and precursor cells and the cells' relationship with the stroma have very specific characteristics. These peculiarities can influence the cells' harvesting and behavior in culture, and the postgraft uptake and further behavior of the gene-modified hematopoietic/precursor cells. In the present mini-review, we shall briefly summarize these characteristics and outline the possible consequences and challenges.

show abstract

“…Wiskott-Aldrich syndrome (WAS), caused by mutations in a cytoskeletal protein, WAS protein (WASp), affects dendritic cell migration and immune synapse formation with T cells [66] but may enhance dendritic cell cross-presentation [67]. Impaired T cell and antibody responses result in the risk of recurrent severe infection.…”

Section: Dendritic Cells In Primary Immunodeficiency Diseasementioning

confidence: 99%

Dendritic cell analysis in primary immunodeficiency

Barge

Collin

2016

Current Opinion in Allergy &Amp; Clinical Immunology

View full text Add to dashboard Cite

Purpose of reviewDendritic cells are specialized antigen-presenting cells which link innate and adaptive immunity, through recognition and presentation of antigen to T cells. Although the importance of dendritic cells has been demonstrated in many animal models, their contribution to human immunity remains relatively unexplored in vivo.Given their central role in infection, autoimmunity, and malignancy, dendritic cell deficiency or dysfunction would be expected to have clinical consequences.Recent findingsHuman dendritic cell deficiency disorders, related to GATA binding protein 2 (GATA2) and interferon regulatory factor 8 (IRF8) mutations, have highlighted the importance of dendritic cells and monocytes in primary immunodeficiency diseases and begun to shed light on their nonredundant roles in host defense and immune regulation in vivo. The contribution of dendritic cell and monocyte dysfunction to the pathogenesis of primary immunodeficiency disease phenotypes is becoming increasingly apparent. However, dendritic cell analysis is not yet a routine part of primary immunodeficiency disease workup.SummaryWidespread uptake of dendritic cell/monocyte screening in clinical practice will facilitate the discovery of novel dendritic cell and monocyte disorders as well as advancing our understanding of human dendritic cell biology in health and disease.

show abstract

WASp-dependent actin cytoskeleton stability at the dendritic cell immunological synapse is required for extensive, functional T cell contacts

Abstract: Novel DC podosomes surround the central MHCII cluster to stabilize the IS; a driver role for the DC actin cytoskeleton.

Cited by 56 publications

References 67 publications

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

Loss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease

Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View

Dendritic cell analysis in primary immunodeficiency

Contact Info

Product

Resources

About