The Rho GTPase Cdc42 Is Essential for the Activation and Function of Mature B Cells

Gerasimčik, Natalija; Dahlberg, Carin; Baptista, Marisa A. P.; Massaad, Michel J.; Geha, Raif S.; Westerberg, Lisa S.; Severinson, Eva

doi:10.4049/jimmunol.1401634

Cited by 25 publications

(32 citation statements)

References 37 publications

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“…Moreover, Cdc42-deficient B cells are impaired in B cell receptor signaling, are unable to mount an antibody response, and have decreased generation of plasma cells (PC) ( 2 , 3 ). Similar to Guo et al, we found that the migratory response to the chemokine CXCL12 was similar in Cdc42-deficient and wild-type (WT) B cells ( 2 , 4 ). When examining cytoskeletal responses, B cells lacking Cdc42 had reduced spreading capacity on antibody-coated surfaces, a response coupled to a particular movement of B cells with formation of long trailing uropods ( 4 ).…”

Section: Introductionsupporting

confidence: 88%

“…The role of one member, Cdc42, on B cell differentiation and function has been studied by us and others. These studies show that Cdc42 is important for B cell differentiation, signal transduction through different receptors, and for the humoral immune response ( 2 – 4 ). Absence of Cdc42 during differentiation in the bone marrow causes an early block in B cell development.…”

Section: Introductionmentioning

confidence: 94%

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The Small Rho GTPases Rac1 and Rac2 Are Important for T-Cell Independent Antigen Responses and for Suppressing Switching to IgG2b in Mice

Gerasimčik

Dahlberg

et al. 2017

Front. Immunol.

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The Rho GTPases Cdc42, Rac1, and Rac2 coordinate receptor signaling to cell adhesion, migration, and proliferation. Deletion of Rac1 and Rac2 early during B cell development leads to failure in B cell entry into the splenic white pulp. Here, we sought to understand the role of Rac1 and Rac2 in B cell functionality and during the humoral antibody response. To circumvent the migratory deficiency of B cells lacking both Rac1 and Rac2, we took the approach to inducibly delete Rac1 in Rac2−/− B cells in the spleen (Rac1BRac2−/− B cells). Rac1BRac2−/− mice had normal differentiation of splenic B cell populations, except for a reduction in marginal zone B cells. Rac1BRac2−/− B cells showed normal spreading response on antibody-coated layers, while both Rac2−/− and Rac1BRac2−/− B cells had reduced homotypic adhesion and decreased proliferative response when compared to wild-type B cells. Upon challenge with the T-cell-independent antigen TNP-conjugated lipopolysaccharide, Rac1BRac2−/− mice showed reduced antibody response. In contrast, in response to the T-cell-dependent antigen sheep red blood cells, Rac1BRac2−/− mice had increased serum titers of IgG1 and IgG2b. During in vitro Ig class switching, Rac1BRac2−/− B cells had elevated germline γ2b transcripts leading to increased Ig class switching to IgG2b. Our data suggest that Rac1 and Rac2 serve an important role in regulation of the B cell humoral immune response and in suppressing Ig class switching to IgG2b.

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Section: Introductionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 94%

The Small Rho GTPases Rac1 and Rac2 Are Important for T-Cell Independent Antigen Responses and for Suppressing Switching to IgG2b in Mice

Gerasimčik

Dahlberg

et al. 2017

Front. Immunol.

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“…We consider compulsory to re‐evaluate the role of other molecules in the humoral immune response. This could be the case for Cdc42 or Rac, which also have a role controlling the actin cytoskeleton, and have been described to modulate the humoral response 18, 21, 43, 44.…”

Section: Resultsmentioning

confidence: 97%

Antigen phagocytosis by B cells is required for a potent humoral response

et al. 2018

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Successful vaccines rely on activating a functional humoral response that results from promoting a proper germinal center (GC) reaction. Key in this process is the activation of follicular B cells that need to acquire antigens and to present them to cognate CD4 T cells. Here, we report that follicular B cells can phagocytose large antigen‐coated particles, a process thought to be exclusive of specialized antigen‐presenting cells such as macrophages and dendritic cells. We show that antigen phagocytosis by B cells is BCR‐driven and mechanistically dependent on the GTPase RhoG. Using Rhog −/− mice, we show that phagocytosis of antigen by B cells is important for the development of a strong GC response and the generation of high‐affinity class‐switched antibodies. Importantly, we show that the potentiation effect of alum, a common vaccine adjuvant, requires direct phagocytosis of alum–antigen complexes by B cells. These data suggest a new avenue for vaccination approaches by aiming to deliver 1–3 μm size antigen particles to follicular B cells.

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“…An additional GTPase identified in EVs was Cdc42, which activates actin polymerization in target cells, coordinating cell migration, proliferation, and survival [50]. Recent reports have shown that Cdc42 to be essential for the activation and function of mature B cells in a mouse model of primary immune deficiency [51]. …”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles from bone marrow‐derived mesenchymal stromal cells support ex vivo survival of human antibody secreting cells

Nguyen

Lewis

Joyner

et al. 2018

J of Extracellular Vesicle

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Extracellular vesicles (EVs) from bone marrow (BM)-derived mesenchymal stromal cells (BM-MSC) are novel mechanisms of cell-cell communication over short and long distances. BM-MSC have been shown to support human antibody secreting cells (ASC) survival ex vivo, but whether the crosstalk between the MSC-ASC interaction can occur via EVs is not known. Thus, we evaluated the role of EVs in ASC survival and IgG secretion. EVs were isolated from irradiated and non-irradiated primary BM-MSC and were quantified. They were further characterized by electron microscopy (EM) and CD63 and CD81 immuno-gold EM staining. Human ASC were isolated via fluorescence-activated cell sorting (FACS) and cultured ex vivo with the EV fractions, the EV-reduced fractions, or conventional media. IgG Elispots were used to measure the survival and functionality of the ASC. Contents of the EV fractions were evaluated by proteomics. We saw that both irradiated and non-irradiated MSC secretome preparations afforded vesicles of a size consistent with EVs. Both preparations appeared comparable in EM morphology and CD63 and CD81 immuno-gold EM. Both irradiated and non-irradiated EV fractions supported ASC function, at 88% and 90%, respectively, by day 3. In contrast, conventional media maintained only 4% ASC survival by day 3. To identify the specific factors that provided in vitro ASC support, we compared proteomes of the irradiated and non-irradiated EV fractions with conventional media. Pathway analysis of these proteins identified factors involved in the vesicle-mediated delivery of integrin signalling proteins. These findings indicate that BM-MSC EVs provide an effective support system for ASC survival and IgG secretion.

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The Rho GTPase Cdc42 Is Essential for the Activation and Function of Mature B Cells

Cited by 25 publications

References 37 publications

The Small Rho GTPases Rac1 and Rac2 Are Important for T-Cell Independent Antigen Responses and for Suppressing Switching to IgG2b in Mice

The Small Rho GTPases Rac1 and Rac2 Are Important for T-Cell Independent Antigen Responses and for Suppressing Switching to IgG2b in Mice

Antigen phagocytosis by B cells is required for a potent humoral response

Extracellular vesicles from bone marrow‐derived mesenchymal stromal cells support ex vivo survival of human antibody secreting cells

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