Sailing to and Docking at the Immune Synapse: Role of Tubulin Dynamics and Molecular Motors

Martín-Cófreces, Noa B.; Sánchez-Madrid, Francisco

doi:10.3389/fimmu.2018.01174

Cited by 43 publications

(41 citation statements)

References 147 publications

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“…Successful T cell activation depends on the accumulation of mitochondria at the IS ( 71 , 72 , 75 ). However, the mechanisms that orchestrate mitochondrial trafficking to the IS are not clear ( 76 ). In neurons, kinesin and dynein motors accomplish anterograde and retrograde trafficking of mitochondria along microtubules ( 77 ).…”

Section: P2y11 and P2x4 Receptors Orchestrate The Accumulation And Acmentioning

confidence: 99%

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function

Ledderose

Junger

2020

Front. Immunol.

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Intracellular ATP is the universal energy carrier that fuels many cellular processes. However, immune cells can also release a portion of their ATP into the extracellular space. There, ATP activates purinergic receptors that mediate autocrine and paracrine signaling events needed for the initiation, modulation, and termination of cell functions. Mitochondria contribute to these processes by producing ATP that is released. Here, we summarize the synergistic interplay between mitochondria and purinergic signaling that regulates T cell functions. Specifically, we discuss how mitochondria interact with P2X1, P2X4, and P2Y11 receptors to regulate T cell metabolism, cell migration, and antigen recognition. These mitochondrial and purinergic signaling mechanisms are indispensable for host immune defense. However, they also represent an Achilles heel that can render the host susceptible to infections and inflammatory disorders. Hypoxia and mitochondrial dysfunction deflate the purinergic signaling mechanisms that regulate T cells, while inflammation and tissue damage generate excessive systemic ATP levels that distort autocrine purinergic signaling and impair T cell function. An improved understanding of the metabolic and purinergic signaling mechanisms that regulate T cells may lead to novel strategies for the diagnosis and treatment of infectious and inflammatory diseases.

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Section: P2y11 and P2x4 Receptors Orchestrate The Accumulation And Acmentioning

confidence: 99%

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function

Ledderose

Junger

2020

Front. Immunol.

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“…CCDC28B interacts and colocalizes with all core BBS proteins at the 20 basal body of ciliated cells 23 . ccdc28b knockdown has been shown to result in impaired cilium elongation both in cultured cells and in vivo in zebrafish, and in developmental defects that recapitulate BBS phenotypes 24 . These observations, taken together with the epistatic effect of heterozygous ccdc28b mutations on disease severity in BBS 19 , have led to the hypothesis that CCDC28B may facilitate BBSome function, however the underlying mechanism is as yet unknown.…”

Section: Discussionmentioning

confidence: 99%

A CVID-associated variant in the ciliogenesis protein CCDC28B disrupts immune synapse assembly

Capitani

Onnis

Finetti

et al. 2020

Preprint

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Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated T cells. We hypothesized that ciliogenesis-related genes might be disease candidates for common variable immunodeficiency with impaired T-cell function (T-CVID). We identified a heterozygous, predicted pathogenic variant in the ciliogenesis protein CCDC28B present with increased frequency in a large CVID cohort. We show that CCDC28B participates in IS assembly by regulating polarized T-cell antigen receptor (TCR) recycling. This involves the CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. The CVID-associated CCDC28BR25W variant failed to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b C211T allele displayed IS defects mapping to this pathway that were corrected by overexpression of the wild-type allele. These results identify a new disease gene in T-CVID and pinpoint CCDC28B as a new player in IS assembly.

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“…The interface between the T cell and antigen‐presenting cell (APC) is known as the immune synapse (IS). Actin polymerization and reorganization at the IS is crucial for directing surface proteins and the recruitment of signaling molecules . While WASp is not required for the initial formation of the IS, F‐actin “foci” polymerization downstream of TCR engagement in the IS is impaired in its absence.…”

Section: Human Disease Caused By Regulators Of the Actin Cytoskeletonmentioning

confidence: 99%

“…Actin polymerization and reorganization at the IS is crucial for directing surface proteins and the recruitment of signaling molecules. 66 While WASp is not required for the initial formation of the IS, F-actin "foci" polymerization downstream of TCR engagement in the IS is impaired in its absence. Formation of these "foci" is important for optimal downstream signaling.…”

Section: Regulators Of the Actin Cytoskeletonmentioning

confidence: 99%

Primary immunodeficiencies caused by mutations in actin regulatory proteins

Janssen

2018

Immunological Reviews

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Summary The identification of patients with monogenic gene defects have illuminated the function of different proteins in the immune system, including proteins that regulate the actin cytoskeleton. Many of these actin regulatory proteins are exclusively expressed in leukocytes and regulate the formation and branching of actin filaments. Their absence or abnormal function leads to defects in immune cell shape, cellular projections, migration, and signaling. Through the study of patients’ mutations and generation of mouse models that recapitulate the patients’ phenotypes, our laboratory and others have gained a better understanding of the role these proteins play in cell biology and the underlying pathogenesis of immunodeficiencies and immune dysregulatory syndromes.

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Sailing to and Docking at the Immune Synapse: Role of Tubulin Dynamics and Molecular Motors

Cited by 43 publications

References 147 publications

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function

A CVID-associated variant in the ciliogenesis protein CCDC28B disrupts immune synapse assembly

Primary immunodeficiencies caused by mutations in actin regulatory proteins

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