title: Humoral immunity and CD4+ Th1 cells are both necessary for a fully protective immune response upon secondary infection with Brucella melitensis.
abstract: Brucella spp are intracellular bacteria that cause brucellosis, one of the most common zoonoses in the world. Given the serious medical consequences of this disease, a safe and effective human vaccine is urgently needed. Efforts to develop this vaccine have been hampered by our lack of understanding of what constitutes a protective memory response against Brucella. In this study, we characterize the cells and signaling pathways implicated in the generation of a protective immune memory response following priming by the injection of heat-killed or live Brucella melitensis 16M. Using a panel of gene-deficient mice, we demonstrated that during a secondary recall response, both the Brucella-specific humoral response and CD4+ Th1 cells must act together to confer protective immunity in the spleen to B. melitensis infection. Humoral protective immunity is induced by the inoculation of both heat-killed and live bacteria, and its development does not require T cells, MyD88/IL-12p35 signaling pathways, or an activation-induced deaminase-mediated isotype switch. In striking contrast, the presence of memory IFN-γ-producing CD4+ Th1 cells requires the administration of live bacteria and functional MyD88/IL-12p35 pathways. In summary, our work identifies several immune markers closely associated with protective immune memory and could help to define a rational strategy to obtain an effective human vaccine against brucellosis.
authors.affiliation: Unité de Recherche en Biologie des Microorganismes, Laboratoire d'Immunologie et de Microbiologie, Institut Namurois des Sciences de la Vie, Université de Namur, 5000 Namur, Belgium;
authors.forename: Marie-Alice
authors.initials: MA
authors.lastname: Vitry
authors.forename: Delphine
authors.initials: D
authors.lastname: Hanot Mambres
authors.forename: Carl
authors.initials: C
authors.lastname: De Trez
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Letesson
authors.forename: Eric
authors.initials: E
authors.lastname: Muraille
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D016470:Bacteremia / Q000276:immunology / Q000517:prevention & control; D002004:Brucella Vaccine / Q000008:administration & dosage / Q000276:immunology; D017347:Brucella melitensis / Q000276:immunology*; D002006:Brucellosis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000276:immunology; D056724:Immunity, Humoral; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology; D062690:Vaccines, Live, Unattenuated / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D002004:Brucella Vaccine; D006183:H-2 Antigens; D053594:Myeloid Differentiation Factor 88; D015164:Vaccines, Inactivated; D062690:Vaccines, Live, Unattenuated; D018664:Interleukin-12; D007371:Interferon-gamma