Humoral immunity and CD4+ Th1 cells are both necessary for a fully protective immune response upon secondary infection with Brucella melitensis

• Published in: The Journal of immunology (1950) 2014-04, Vol.192 (8), p.3740-3752
• Main Authors: Vitry, Marie-Alice, Hanot Mambres, Delphine, De Trez, Carl, Akira, Shizuo, Ryffel, Bernhard, Letesson, Jean-Jacques, Muraille, Eric
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Bacterial - immunology; Antibody Specificity - immunology; Bacteremia - immunology; Bacteremia - prevention & control; Brucella melitensis - immunology; Brucella Vaccine - administration & dosage; Brucella Vaccine - immunology; Brucellosis - immunology; Brucellosis - metabolism; Brucellosis - prevention & control; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; H-2 Antigens - immunology; Immunity, Humoral; Immunologic Memory; Interferon-gamma - biosynthesis; Interleukin-12 - metabolism; Mice; Mice, Knockout; Myeloid Differentiation Factor 88 - metabolism; Phenotype; Signal Transduction; Spleen - cytology; Spleen - immunology; Spleen - microbiology; Th1 Cells - immunology; Th1 Cells - metabolism; Vaccines, Inactivated - administration & dosage; Vaccines, Inactivated - immunology; Vaccines, Live, Unattenuated - administration & dosage; Vaccines, Live, Unattenuated - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302561

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.