Human plasma cells express granzyme B

Abstract

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...

Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties

“…61 Interestingly, CD138 has also been shown to be associated with GzmB production, regulatory activity, and IL-21 dependence. 57 In conclusion, we have demonstrated that TOLs have a higher absolute number of GzmB + B cells with a plasma cell2like phenotype and with dose-dependent suppressive properties through the GzmB pathway. B cells decrease T cell proliferation and induce their apoptosis, two processes that may contribute to a tolerogeneic environment.…”

“…These data are reinforced by the effective STAT3 phosphorylation in B cells from tolerant recipients, 14 a key signal for the generation of GzmB activated B cells. 57 Finally, the fact that tolerant recipients have a lower level of IL-21 + CD4 + T cells, and that B cells from these patients alone (and not HVs and STAs) increase IL-21 production by CD4 + T cells, strongly suggests a negative feedback loop in these patients, increasing excessive B cell activation and inflammation and allowing regulation to take place. Bregs are able to control the immune response, but an excessive reaction from these cells may also promote tumor cell growth or chronic infection.…”

“…Moreover, when B cells are added to the coculture, IL-21-producing T cells increase significantly and there is greater production of IL-21 by T cells from TOLs. IL-21 is a key cytokine for GzmB gene transcription, 26,57 which suggests that the increase in GzmB + B cells in blood from tolerant recipients may be due to a direct effect of IL-21. These data are reinforced by the effective STAT3 phosphorylation in B cells from tolerant recipients, 14 a key signal for the generation of GzmB activated B cells.…”

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma

“…Moderate positivity for granzyme B was observed in the cytoplasm of immune cells in the stroma (mainly plasma cells and mast cells, 19,20 ) of less than half of the samples (33% unpretreated, 43% pretreated) (Fig. 2E).…”

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

“…Interestingly, it has been reported in humans that granzyme B + B cells accumulated specifically in tissues and have been suggested to play a critical role in early antiviral immune responses, in the regulation of autoimmune mechanisms, and in cancer immunosurveillance (45)(46)(47). Additionally, it has recently been shown that BCR and IL-21 signaling without an efficient CD40-CD40L ligation leads to the generation of granzyme B + B cells that induce immune dysfunction in solid tumor eradication (45,(48)(49)(50) or in HIV patients (51).…”