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Regulatory B-Cells Are Enriched Within the IgM Memory and Transitional Subsets in Healthy Donors but Deficient In Chronic Graft-Versus-Host Disease

Ahmad Khoder, Anushruti Sarvaria, Abdullah Alsuliman, Claude Chew, Takuya Sekine, Nichola Cooper, Stephan Mielke, Hugues de Lavallade, Muharrem Muftuoglu, Irina Fernandez Curbelo, Enli Liu, Paolo A. Muraro, Amin Alousi, Kate Stringaris, Simrit Parmar, Nina Shah, Hila Shaim, Eric Yvon, Jeffrey Molldrem, Rayne Rouce, Richard Champlin, Ian McNiece, Claudia Mauri, Elizabeth J. Shpall and Katayoun Rezvani

Key points

  • Human IgM memory B cells possess immunoregulatory properties analogous to transitional B cells.

  • IL 10 producing B cells are deficient in cGVHD.

Abstract

A subset of regulatory B cells (Bregs) in mice negatively regulate T cell immune responses through the secretion of regulatory cytokines such as IL-10 and direct cell-cell contact, and have been linked to experimental models of autoimmunity, inflammation, and cancer in mice. However, the regulatory function of Bregs in human disease is much less clear unclear. Here we demonstrate that B cells with immunoregulatory properties are enriched within both the CD19+IgM+CD27+ memory and CD19+CD24hiCD38hi transitional B cell subsets in healthy human donors. Both subsets suppressed the proliferation and interferon-γ production of CD3/CD28-stimulated autologous CD4+ T cells in a dose-dependent manner and both relied on IL-10 secretion as well as cell-cell contact, likely mediated through CD80 and CD86, to support their full suppressive function. Moreover, following allogeneic stem cell transplantation, Bregs from patients with chronic graft-versus-host disease (cGVHD) were less frequent and less likely to produce lL-10 than were Bregs from healthy donors and patients without cGVHD. These findings suggest that Bregs may be involved in the pathogenesis of cGVHD and support future investigation of regulatory B-cell–based therapy in the treatment of this disease.

  • Submitted April 21, 2014.
  • Accepted July 6, 2014.