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* Deutsches Rheuma-ForschungsZentrum;
Max Planck Institute of Infection Biology, Berlin, Germany;
University of Edinburgh, Institute of Immunology and Infection Research, School of Biological Sciences, Edinburgh, United Kingdom; and
Unité de Recherche Associée Centre National de la Recherche Scientifique 1961, Institut Pasteur, Paris, France
TLR sense microbial infections, and control activation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and the TLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediated inflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies in MyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in B cells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE. Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for disease initiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in B cells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of B cells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88 signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cells and is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbial products via TLR to suppression of a T cell-mediated autoimmune disease.
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1 This work was supported by the Deutsche Forschungsgemeinschaft (SFB-650), Medical Research Council U.K., Institut Pasteur, Association pour la Recherche sur la Sclerose en Plaques, and Association pour la Recherche sur le Cancer. Y.H. was funded by Association pour la Recherche sur le Cancer. S.M.A. is a Medical Research Council senior research fellow.
2 V.L., K.H., and T.R. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Simon Fillatreau, Deutsches Rheuma-ForschungsZentrum, Charitéplatz 1, 10117 Berlin, Germany. E-mail address: fillatreau{at}drfz.de
4 Abbreviations used in this paper: DC, dendritic cell; SLE, systemic lupus erythematosus; MS, multiple sclerosis; MOG, myelin oligodendrocyte glycoprotein; EAE, experimental autoimmune encephalomyelitis.
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