Characterization of IL-10-producing B cells and their suppressive activities during primary and secondary Salmonella typhimurium infection
Final Report Abstract
B lymphocytes and their activated antibody-secreting progeny, called plasma cells, play essential roles in the protection of the host from infectious diseases. Antibodies are highly specific molecules that can bind to and neutralize pathogens. During the last 20 years, it has been recognized that B cells contribute to immunity not only through the production of antibodies, but also through the secretion of cytokines, which are small secreted molecules mediating the communication among cells of the immune system as well as with cells of their environment. In particular, it was discovered that B cells could inhibit the activity of the immune system through the production of anti-inflammatory cytokines such as interleukin (IL)-10. The importance of this suppressive function has now been recognized in infectious, autoimmune, allergic, and malignant diseases. There is currently considerable interest in identifying the B cells providing such IL-10-mediated regulatory function because the ablation of such cells could be useful to increase immunity against pathogens and cancer. In contract, favouring an augmentation of the abundance of such cells could help dampening unwanted disease-driving immunity in autoimmune or allergic pathologies. The aim of this project was to characterize the B cell sub-population producing IL-10 in a suppressive manner in a model of infection. This led to the identification of a novel subset of plasma cells specialized in the production of IL-10 upon activation. These cells are distinct from other plasma cells by their expression of the inhibitory surface receptor LAG-3, the repertoire of their B cell receptor for antigen (BCR), and their epigenome. In particular, they have the lowest level of DNA methylation at the Il10 locus of all B cell subsets found in the organism, implying that they are the most prepared and specialized for IL-10 production. Remarkably, these plasma cells also express other inhibitory surface receptors including CD200, PD-L1, and PD-L2, which are known, for instance, to be involved in the inhibition of anti-tumor immunity so that reagents blocking the interaction between PD-1 and PD-L1 as well as PD-L2 have led to a revolution in anti-tumor therapy. These plasma cells are constitutively generated in the host, independently of any immune challenge, possibly in response to signals provided by damaged cells including damaged red blood cells. Accordingly, their number increases greatly with age, which is known to be associated with an accumulation of damaged cells, particularly senescent cells, in tissues. Situations in which these cells are present in increased amounts are associated with an impaired vaccine response. In sum, this project led to the discovery of natural regulatory plasma cells. The identification of the human counterpart of these cells could have important consequences.
Publications
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2014. From the regulatory functions of B cells to the identification of cytokine-producing plasma cell subsets. Curr Opin Immunol. 28: 77
Van Dang, D., E. Hilgenberg, S. Ries, P. Shen, and S. Fillatreau
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2014. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 507: 366
Shen, P., Roch, T., V. Lampropoulou, R.A. O’Connor, U. Stervbo, E. Hilgenberg, Y. Jaimes, C. Daridon, R. Lui, L. Jouneau, P. Boudinot, S. Ries, Y. Miyazaki, M.D. Leech, R.C. McPherson, S. Wirtz, M. Neurath, V.D. Dang, 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, and S. Fillatreau
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2015. Antibody-independent functions of B cells: a focus on cytokines. Nat Rev Immunol. 15:441
Shen, P, and S. Fillatreau
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2015. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol. Rev. 269: 130
Lino, A.C., T. Dörner, A. Bar-Or, and Fillatreau S.
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2016. Regulatory roles of B cells in infectious diseases. Clin Exp Rheumatol. 34 :1
Fillatreau, S.
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2018. B cells and their cytokine activities - Implications in human diseases. Clinical Immunology. 186:26
Fillatreau, S.
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2018. LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells. Immunity. 49: 120
Lino, A.C., Dang, V.D., Lampropoulou, V., Welle, A., Joedicke, J., Pohar, J., Simon, Q., Thalmensi, J., Baures, A., Flühler, V., Sakwa, I., Stervbo, U., Ries, S., Jouneau, L., Boudinot, P., Tsubata, T., Adachi, T., Hutloff, A., Dörner, T., Zimber-Strobl, U., de Vos, A.F., Dahlke, K., Loh, G., Korniotis, S., Goosmann, C., Weill, J.C., Reynaud, C.A., Kaufmann, S.H.E., Walter, J., Fillatreau, S.
