In vitro generation of long-lived human plasma cells

Mario Cocco, Sophie Stephenson, Matthew A Care, Darren Newton, Nicholas A Barnes, Adam Davison, Andy Rawstron, David R Westhead, Gina M Doody, Reuben M Tooze

Research output: Contribution to journalArticlepeer-review

Abstract

Plasma cells (PCs), the terminal effectors of humoral immunity, are short-lived unless supported by niche environments in which they may persist for years. No model system has linked B cell activation with niche function to allow the in vitro generation of long-lived PCs. Thus, the full trajectory of B cell terminal differentiation has yet to be investigated in vitro. In this article, we describe a robust model for the generation of polyclonal long-lived human PCs from peripheral blood B cells. After a proliferative plasmablast phase, PCs persist in the absence of cell division, with viability limited only by elective culture termination. Conservative predictions for PC life expectancy are 300 d, but with the potential for significantly longer life spans for some cells. These long-lived PCs are preferentially derived from memory B cells, and acquire a CD138(high) phenotype analogous to that of human bone marrow PCs. Analysis of gene expression across the system defines clusters of genes with related dynamics and linked functional characteristics. Importantly, genes in these differentiation clusters demonstrate a similar overall pattern of expression for in vitro and ex vivo PCs. In vitro PCs are fully reprogrammed to a secretory state and are adapted to their secretory load, maintaining IgG secretion of 120 pg/cell/day in the absence of XBP1 mRNA splicing. By establishing a set of conditions sufficient to allow the development and persistence of mature human PCs in vitro, to our knowledge, we provide the first platform with which to sequentially explore and manipulate each stage of human PC differentiation.

Original languageEnglish
Pages (from-to)5773-85
Number of pages13
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume189
Issue number12
DOIs
Publication statusPublished - 15 Dec 2012

Keywords

  • Adult
  • B-Lymphocyte Subsets
  • Bone Marrow Cells
  • Cell Aging
  • Cell Differentiation
  • Cells, Cultured
  • Gene Expression Regulation
  • Humans
  • Immunologic Memory
  • Immunophenotyping
  • Lymphocyte Activation
  • Plasma Cells
  • Predictive Value of Tests
  • Time Factors
  • Comparative Study
  • Journal Article
  • Research Support, Non-U.S. Gov't

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