Abstract
The functions of bone marrow plasma cells (BMPC) beyond antibody production are not fully elucidated and distinct subsets of BMPC suggest potential different functions. Phenotypic differences were identified for human BMPC depending on CD19 expression. Since CD19 is a co-stimulatory molecule of the B-cell-receptor (BCR), and IgA+ and IgM+ BMPC express the BCR on their surface, we here studied whether CD19 expression affects cellular responses, such as BCR signaling and the expression of checkpoint molecules. We analyzed 132 BM samples from individuals undergoing routine total hip arthroplasty. We found that both CD19+ and CD19− BMPC expressed BCR signaling molecules. Notably, the BCR-associated kinase spleen tyrosine kinase (SYK) including pSYK was higher expressed in CD19+ BMPC compared to CD19− BMPC. BCR stimulation also resulted in increased kinase phosphorylation downstream of the BCR while expression of CD19 remained stable afterwards. Interestingly, the BCR response was restricted to IgA+ BMPC independently of CD19 expression. With regard to the expression of checkpoint molecules, CD19− BMPC expressed higher levels of co-inhibitory molecule programmed cell death protein-1 (PD-1) than CD19+ BMPC. IgA+ BMPC characteristically upregulated PD-1 upon BCR stimulation in contrast to other PC subsets and inhibition of the kinase SYK abrogated PD-1 upregulation. In contrast, expression of PD-1 ligand, B and T lymphocyte attenuator (BTLA) and CD28 did not change upon BCR activation of IgA+ BMPC. Here, we identify a distinct characteristic of IgA+ BMPC that is independent of the phenotypic heterogeneity of the subsets according to their CD19 expression. The data suggest that IgA+ BMPC underlie different regulatory principles and/or exert distinct regulatory functions.
Highlights
Human serum antibody titers are relatively stable and exhibit half-lives ranging from years to decades [1]
To assess whether CD19+ and CD19− bone marrow plasma cells (BMPC) both have the prerequisites for BCR signaling, CD19+ and CD19− BMPC gene expression was analyzed for BCR-associated molecules
Signaling, the analysis showed that transcripts of molecules relevant for BCR signaling are found in both CD19+ and CD19− BMPC, among them e.g. BCR components (CD79A, CD79B), BCR co-stimulating receptors (CD21, CD81), protein tyrosine kinases (PTKs) and protein serine/threonine kinases (PSKs, spleen tyrosine kinase (SYK), PLCG2, BTK, AKT3) and BCR associated phosphatases (PTPN6, INPP5D)
Summary
Human serum antibody titers are relatively stable and exhibit half-lives ranging from years to decades [1]. They are produced by plasma cells (PC) located in the bone marrow (BM), which have a unique transcriptome with >70% of transcripts encoding the immunoglobulin heavy (IgH) and light (IgL) chains [2]. Of these BMPC, a subset is considered to be long-lived producing IgG with half-live times above 10.000 years [1, 3]. Low frequencies of CD19low/CD19− plasmablasts have been identified during the acute response to influenza vaccination and steady state [6]
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