Activated Mouse B Cells Lack Expression of Granzyme B

Hagn, Magdalena; Belz, Gabrielle T.; Kallies, Axel; Sutton, Vivien R.; Thia, Kevin; Tarlinton, David M.; Hawkins, Edwin D.; Trapani, Joseph A.

doi:10.4049/jimmunol.1103285

Cited by 31 publications

(25 citation statements)

References 51 publications

(57 reference statements)

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“…Furthermore, GrB-secreting B cells possess cytotoxic potential in the absence of perforin expression (64), which is thought to contribute to their immunoregulatory potential (66). In contrast, Hagn et al (67) could not detect GrB expression in resting or activated murine B cells.…”

Section: Unresolved Questionsmentioning

confidence: 90%

Granzymes Regulate Proinflammatory Cytokine Responses

Wensink

Hack

Bovenschen

2015

The Journal of Immunology

120

153

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Granzymes (Grs) are serine proteases mainly produced by cytotoxic lymphocytes and are traditionally considered to cause apoptosis in tumor cells and virally infected cells. However, the cytotoxicity of several Grs is currently being debated, and additional, predominantly extracellular, functions of Grs in inflammation are emerging. Extracellular soluble Grs are elevated in the circulation of patients with autoimmune diseases and infections. Additionally, Grs are expressed by several types of immune cells other than cytotoxic lymphocytes. Recent research has revealed novel immunomodulatory functions of Grs. In this review, we provide a comprehensive overview on the role of Grs in inflammation, highlighting their role in cytokine induction and processing.

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Section: Unresolved Questionsmentioning

confidence: 90%

Granzymes Regulate Proinflammatory Cytokine Responses

Wensink

Hack

Bovenschen

2015

The Journal of Immunology

120

153

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“…This is mostly due to the fact that activated mouse B cells lack GrzB [39], suggesting that GrzB biology may not be directly translated from one species to another. Thus, we will need to develop novel in vivo systems to understand fully the role of GrzB in PC development and function in humans.…”

Section: Discussionmentioning

confidence: 99%

Human plasma cells express granzyme B

Narayanan

Kang

et al. 2013

Eur J Immunol

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While studying the plasma cell (PC) compartment in human tonsils, we identified that immunoglobulin kappa or lambda chain-expressing PCs are the main cells expressing granzyme B (GrzB). In vitro studies revealed that activated B cells differentiated into GrzBexpressing PCs when co-cultured with macrophages and follicular helper T cells. This effect could be reproduced on combined stimulation of IL-15 (produced by macrophages) and IL-21 (produced by T follicular helper cells) in a STAT3-dependent manner. Whereas IL-21 triggers the transcription of mRNA of GrzB, IL-15 synergizes the translation of GrzB proteins. The precise role of GrzB in PC biology remains to be understood and studies in mice will not help as their PCs do not express GrzB. Keywords: B cells r Granzyme B (GrzB) r Plasma cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTo mount prompt Ab responses, B cells encounter antigens in secondary lymphoid organs, such as LNs, spleen, Peyer's patches, and tonsils [1]. B-cell activation is initiated through B-cell receptor (BCR) engagement by antigens exposed on the surface of presenting cells, including follicular dendritic cells [2], dendritic cells Correspondence: Dr. Wei Xu e-mail: wei.xu.wx6@roche.com [3][4][5][6], and macrophages [7][8][9][10]. Following BCR-mediated capture, the antigens are targeted to processing compartments that facilitate the binding of Ag-derived peptides onto MHC molecules for presentation to cognate T cells [11]. These B-T-cell interactions primarily occur in two major locations: at the follicular borders of T-and B-cell zones [12,13], and within the germinal center (GC) [14][15][16]. Thus, a typical humoral response leading to the generation of plasma cells (PCs) depends on the microarchitecture where B cells, T cells, and APCs congregate to provide niches for differentiation of PCs [17].C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 276Wei Xu et al. Eur. J. Immunol. 2014. 44: 275-284 Figure 1. Human tonsil harbors GrzB-expressing PCs. A confocal image of human tonsil section for GrzB + and Ig κ light chain + PCs. Red staining: GrzB-AF568; green staining: κ light chain-AF488; light blue staining: DAPI; dark blue staining: CD3. Scale bar: 250 or 10 μM (for 63× magnification). Similar images were obtained from >8 different tonsils from different donors.Typically, terminally differentiated PCs reside in the extrafollicular foci of peripheral lymphoid organs, and in the BM where peripheral PCs home to become long-lived PCs [18][19][20][21]. While the complexity of PC development has been extensively studied in mice, it is unclear whether the same mechanisms operate for human PC differentiation. In particular, IL-10 acts as a potent B-cell differentiation factor in humans but not in mice [22]. Furthermore, it is now appreciated that PCs may be composed of subsets [23][24][25]. It is generally accepted that the more mature PCs are associated with the lowest levels of CD19, CD20...

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“…In vivo immunization and detection of NP-specific antibody via enzyme-linked immunosorbent assay was performed as described in Hagn et al 41 Cell culture of mouse B cells. Mouse B cells were prepared, CFSE labelled and cultured as described in Hawkins et al 37 Cell numbers were determined by reference to fluorescence-activated cell sorting calibration beads as described in Hawkins et al 20 B cells were typically 495% B220 þ , CD19 þ , IgM þ , IgD þ as determined by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity

et al. 2013

Self Cite

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The production of protective antibody requires effective signalling of naive B cells following encounter with antigen, and the divergence of responding B lymphocytes into distinct lineages. Polarity proteins have recently been proposed as important mediators of both the initial B cell response, and potentially of asymmetric cell division. Here we show that, although polarity proteins of the Scribble complex, Scribble, Dlg1 and Lgl1, are expressed and polarized during early B cell activation, their deficiency has no effect on the in vivo outcome of immunization or challenge with influenza infection. Furthermore, we find a striking correlation in the differentiation outcome of daughters of single founder B cells in vitro. Taken together, our results indicate that B cell differentiation does not require polarity proteins of the Scribble complex, and the findings do not support a role for asymmetric cell division in B cell activation and differentiation.

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Activated Mouse B Cells Lack Expression of Granzyme B

Cited by 31 publications

References 51 publications

Granzymes Regulate Proinflammatory Cytokine Responses

Granzymes Regulate Proinflammatory Cytokine Responses

Human plasma cells express granzyme B

Regulation of asymmetric cell division and polarity by Scribble is not required for humoral immunity

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