B Cells Adapt Their Nuclear Morphology to Organize the Immune Synapse and Facilitate Antigen Extraction

Ulloa, Romina; Corrales, Oreste; Cabrera-Reyes, Fernanda; Jara‐Wilde, Jorge; Sáez, Juan José; Rivas, Christopher; Lagos, Jonathan; Härtel, Steffen; Quiroga, Clara; Yuseff, María-Isabel; Diaz-Muñoz, Jheimmy

doi:10.3389/fimmu.2021.801164

Cited by 7 publications

(6 citation statements)

References 62 publications

(79 reference statements)

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“…We observed that this process is characterized by two classes of events: a first phase (in the first 3.5 min), where F-actin is strongly polymerized at the site of contact, leading to antigen accumulation and production of DAG as a result of BCR signaling, and a second phase during which the centrosome is reoriented toward the immune synapse together with the Golgi apparatus and lysosomes while the nucleus undergoes a rotation followed by backward transport. The timescales we found for late polarization events are shorter than the ones measured for B cells in other systems (e.g., centrosome polarized in 30 min [ Yuseff et al, 2011 ], nucleus fully polarized in 30 min [ Ulloa et al, 2022 ], lysosomes maximally clustered in 40 min [ Spillane and Tolar, 2018 ]) and much closer to results found in T cells ( Gawden-Bone et al, 2018 ; Yi et al, 2013 ; Hooikaas et al, 2020 ), possibly due to the properties of the substrate that we used for antigen presentation. We found that F-actin polymerization is only needed for the first phase, in contrast to microtubules that not only control centrosome and organelle repositioning, but further maintain a unique polarity axis by restricting actin nucleation to the immune synapse.…”

Section: Discussionsupporting

confidence: 66%

Microtubules restrict F-actin polymerization to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

Pineau

Pinon

Mesdjian

et al. 2022

eLife

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Immune synapse formation is a key step for lymphocyte activation. In B lymphocytes, the immune synapse controls the production of high-affinity antibodies, thereby defining the efficiency of humoral immune responses. While the key roles played by both the actin and microtubule cytoskeletons in the formation and function of the immune synapse have become increasingly clear, how the different events involved in synapse formation are coordinated in space and time by actin-microtubule interactions is not understood. Using a microfluidic pairing device, we studied with unprecedented resolution the dynamics of the various events leading to immune synapse formation and maintenance in murine B cells. Our results identify two groups of events, local and global dominated by actin and microtubules dynamics, respectively. They further highlight an unexpected role for microtubules and the GEF-H1-RhoA axis in restricting F-actin polymerization at the lymphocyte-antigen contact site, thereby allowing the formation and maintenance of a unique competent immune synapse.

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Section: Discussionsupporting

confidence: 66%

Microtubules restrict F-actin polymerization to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

Pineau

Pinon

Mesdjian

et al. 2022

eLife

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“…We observed that Vti1b was specifically polarised to the IS upon BCR activation ( Figure 3 ). It has been widely reported that lymphocytes polarise the endocytic/exocytic machinery, as well as other organelles, such as the Golgi apparatus, to the IS ( del Valle Batalla et al, 2018 ; Duchez et al, 2011 ; Ulloa et al, 2022 ; Yuseff et al, 2011 ). Thus, it was not unexpected that Vti1b, which mainly resides in the Golgi and lysosomes, would polarise to the IS.…”

Section: Discussionmentioning

confidence: 99%

The SNARE protein Vti1b is recruited to the sites of BCR activation but is redundant for antigen internalisation, processing and presentation

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Tejeda-González

Cunha

et al. 2022

Front. Cell Dev. Biol.

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In order to fulfil the special requirements of antigen-specific activation and communication with other immune cells, B lymphocytes require finely regulated endosomal vesicle trafficking. How the endosomal machinery is regulated in B cells remains largely unexplored. In our previous proximity proteomic screen, we identified the SNARE protein Vti1b as one of the strongest candidates getting accumulated to the sites of early BCR activation. In this report, we follow up on this finding and investigate the localisation and function of Vti1b in B cells. We found that GFP-fused Vti1b was concentrated at the Golgi complex, around the MTOC, as well as in the Rab7+ lysosomal vesicles in the cell periphery. Upon BCR activation with soluble antigen, Vti1b showed partial localization to the internalized antigen vesicles, especially in the periphery of the cell. Moreover, upon BCR activation using surface-bound antigen, Vti1b polarised to the immunological synapse, colocalising with the Golgi complex, and with lysosomes at actin foci. To test for a functional role of Vti1b in early B cell activation, we used primary B cells isolated from Vit1b-deficient mouse. However, we found no functional defects in BCR signalling, immunological synapse formation, or processing and presentation of the internalized antigen, suggesting that the loss of Vti1b in B cells could be compensated by its close homologue Vti1a or other SNAREs.

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“…The distribution of lysosomes within Z sections was previously described [ 37 ]. Values of lysosomes were calculated by measuring their mean fluorescence intensity (MFI) in the cell at each z-slice (0.2 µm) from the immune synapse (defined by the contact area on antigen coated dishes) to the top of the cell.…”

Section: Methodsmentioning

confidence: 99%

Autophagy Induced by Toll-like Receptor Ligands Regulates Antigen Extraction and Presentation by B Cells

Lagos

Sagadiev

Díaz

et al. 2022

Cells

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The engagement of B cells with surface-tethered antigens triggers the formation of an immune synapse (IS), where the local secretion of lysosomes can facilitate antigen uptake. Lysosomes intersect with other intracellular processes, such as Toll-like Receptor (TLR) signaling and autophagy coordinating immune responses. However, the crosstalk between these processes and antigen presentation remains unclear. Here, we show that TLR stimulation induces autophagy in B cells and decreases their capacity to extract and present immobilized antigens. We reveal that TLR stimulation restricts lysosome repositioning to the IS by triggering autophagy-dependent degradation of GEF-H1, a Rho GTP exchange factor required for stable lysosome recruitment at the synaptic membrane. GEF-H1 degradation is not observed in B cells that lack αV integrins and are deficient in TLR-induced autophagy. Accordingly, these cells show efficient antigen extraction in the presence of TLR stimulation, confirming the role of TLR-induced autophagy in limiting antigen extraction. Overall, our results suggest that resources associated with autophagy regulate TLR and BCR-dependent functions, which can finetune antigen uptake by B cells. This work helps to understand the mechanisms by which B cells are activated by surface-tethered antigens in contexts of subjacent inflammation before antigen recognition, such as sepsis.

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B Cells Adapt Their Nuclear Morphology to Organize the Immune Synapse and Facilitate Antigen Extraction

Cited by 7 publications

References 62 publications

Microtubules restrict F-actin polymerization to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

Microtubules restrict F-actin polymerization to the immune synapse via GEF-H1 to maintain polarity in lymphocytes

The SNARE protein Vti1b is recruited to the sites of BCR activation but is redundant for antigen internalisation, processing and presentation

Autophagy Induced by Toll-like Receptor Ligands Regulates Antigen Extraction and Presentation by B Cells

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