Editors' ChoiceImmunology

Suppressed by B Cells

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Science Signaling  25 Mar 2014:
Vol. 7, Issue 318, pp. ec79
DOI: 10.1126/scisignal.2005296

The production of antibodies by B cells positively contributes to the adaptive immune response. However, B cells can also have an immunosuppressive effect through the production of the cytokine interleukin-10 (IL-10). To identify additional immunosuppressive factors produced by B cells, Shen et al. screened genes encoding secreted proteins that were differentially expressed in B cells stimulated with ligands for the Toll-like receptor 4 (TLR4) and CD40 but not those stimulated only with the TLR4 ligand, which increases IL-10 production. The authors identified Epstein barr virus-induced gene 3 (Ebi3), which encodes a protein that dimerizes with either p28 to form IL-27 or with p35 to form IL-35. Analysis of various B cell–specific knockout mice revealed that lack of IL-35 production specifically in a mouse model of multiple sclerosis (EAE mice) resulted in worse disease, which was associated with increased infiltration of activated cytotoxic T cells in the central nervous system. Furthermore, B cells lacking the ability to produce IL-35 isolated from the EAE mice also exhibited increased markers associated with antigen presentation and were more potent at stimulating the proliferation of and production of inflammatory cytokines from T cells isolated from the same mice. Although lack of immunosuppression worsens autoimmune disease, it can improve resistance to pathogens. Indeed, the B cell–specific knockout mice that could not produce IL-35, because they lacked the gene for either p35, Ebi3, or CD40, were resistant to Salmonella infection, which was associated with increased inflammatory responses of T cells toward the pathogen. Analysis of single B cells from wild-type mice infected with Salmonella revealed distinct IL-10– and IL-35–producing populations of B cells, both of which were positive for markers of mature plasma cells, which are the antibody-secreting cells. Thus, plasma cells not only promote the adaptive immune response but also help to keep this response in check by producing immunosuppressive cytokines.

P. Shen, T. Roch, V. Lampropoulou, R. A. O’Connor, U. Stervbo, E. Hilgenberg, S. Ries, V. D. Dang, Y. Jaimes, C. Daridon, R. Li, L. Jouneau, P. Boudinot, S. Wilantri, I. Sakwa, Y. Miyazaki, M. D. Leech, R. C. McPherson, S. Wirtz, M. Neurath, K. Hoehlig, E. Meinl, A. Grützkau, J. R. Grün, K. Horn, A. A. Kühl, T. Dörner, A. Bar-Or, S. H. E. Kaufmann, S. M. Anderton, S. Fillatreau, IL-35–producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 507, 366–370 (2014). [PubMed]