The Role of Bone Marrow-Derived Stromal Cells in the Maintenance of Plasma Cell Longevity

Wols, Heather A. Minges; Underhill, Gregory H.; Kansas, Geoffrey S.; Witte, Pamela L.

doi:10.4049/jimmunol.169.8.4213

Cited by 253 publications

(113 citation statements)

References 58 publications

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“…For instance, the integrin α 4 β 1 (VLA-4) has been described as a key factor for the generation of long-lived PC [14,44]. Reports show that these cells rely on a combination of soluble and contact-mediated mechanisms to fulfill hematopoietic and immunomodulatory functions [45–47].…”

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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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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“…Recent reports have indicated that there are functionally unique subpopulations of Ab-secreting cells (ASC) 3 present within mammals, including the plasmablast (7,8), the short-lived plasma cell (9,10), and the long-lived plasma cell (11)(12)(13)(14)(15). The plasmablast is an ASC that is distinguished from plasma cells by its ability to proliferate, its short half-life, and its low levels of CD138, B220, and presence of c-Myc (7, 16 -18).…”

mentioning

confidence: 99%

Plasmablast and Plasma Cell Production and Distribution in Trout Immune Tissues

Bromage

Kaattari

Zwollo

et al. 2004

The Journal of Immunology

172

134

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These studies describe the in vitro and ex vivo generation of plasmablasts and plasma cells in trout (Oncorhynchus mykiss) peripheral blood and splenic and anterior kidney tissues. Cells were derived either from naive trout and cultured with the polyclonal activator, Escherichia coli LPS, or from trout that had been immunized with trinitrophenyl-keyhole limpet hemocyanin. Hydroxyurea was used to resolve populations of replicating (plasmablast) and nonreplicating (plasma cell) Ab-secreting cells (ASC). Complete inhibition of Ig secretion was only observed within the PBL. Both anterior kidney and splenic lymphocytes possessed a subset of ASCs that were hydroxyurea resistant. Thus, in vitro production of plasma cells appears to be restricted to the latter two tissues, whereas peripheral blood is exclusively restricted to the production of plasmablasts. After immunization with trinitrophenyl-keyhole limpet hemocyanin, specific ASC could be isolated from all immune organs; however, the anterior kidney contained 98% of all ASC. Late in the response (>10 wk), anterior kidney ASC secreted specific Ab for at least 15 days in culture, indicating that they were long-lived plasma cells. Cells from spleen and peripheral blood lost all capacity to secrete specific Ab in the absence of Ag. Late in the Ab response, high serum titer levels are solely the result of Ig secretion from anterior kidney plasma cells.

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“…Increased integrin trans-regulation might also have utilities beyond tumor immunotherapy. Migration and survival of long-lived plasma cells in the bone marrow appears to be dependent on α4 and αLβ2 integrins (31–35) and could involve integrin trans-regulation. Thus, enhanced integrin trans-regulation offers a new approach to selectively potentiate β2 integrin-mediated homing of lymphocytes and plasma cells.…”

Section: Resultsmentioning

confidence: 99%

Fine-tuning Tumor Immunity with Integrin Trans-regulation

Cantor

Rose

Slepak

et al. 2015

Cancer Immunology Research

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Inefficient T-cell homing to tissues limits adoptive T-cell immunotherapy of solid tumors. αLβ2 and α4β1 integrins mediate trafficking of T cells into tissues via engagement of ICAM-1 and VCAM-1, respectively. Inhibiting Protein Kinase A(PKA)-mediated phosphorylation of α4 integrin in cells results in an increase in αLβ2-mediated migration on mixed ICAM-1-VCAM-1 substrates in vitro, a phenomenon termed “integrin trans-regulation.” Here we created an α4(S988A)-bearing mouse, which precludes PKA-mediated α4 phosphorylation, to examine the effect of integrin trans-regulation in vivo. The α4(S988A) mouse exhibited a dramatic and selective increase in migration of lymphocytes, but not myeloid cells, to sites of inflammation. Importantly, we found that the α4(S988A) mice exhibited a marked increase in T cell entry into and reduced growth of B16 melanomas, consistent with anti-tumor roles of infiltrating T cells and pro-growth functions of tumor-associated macrophages. Thus, increased α4 trans-regulation of αLβ2 integrin function biases leukocyte emigration towards lymphocytes relative to myeloid cells and enhances tumor immunity.

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The Role of Bone Marrow-Derived Stromal Cells in the Maintenance of Plasma Cell Longevity

Cited by 253 publications

References 58 publications

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

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

Plasmablast and Plasma Cell Production and Distribution in Trout Immune Tissues

Fine-tuning Tumor Immunity with Integrin Trans-regulation

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