Memory CD8+ T cells mediate antibacterial immunity via CCL3 activation of TNF/ROI+ phagocytes

• DOI: 10.1084/jem.20070204
• Publication Date: 2007-08-14T00:40:14Z
• Authors: Emilie Narni-Manc...; Laura Campisi; Delphine Bassand; Julie Cazareth; Pierre Gounon; Nicolas Glaichenhaus; Grégoire Lauvau
• Keywords: Cytotoxicity, Immunologic; MESH: Neutrophils; CD8-Positive T-Lymphocytes; MESH: Listeria monocytogenes; MESH: Phagocytes; Mice; MESH: Leishmania major; 0302 clinical medicine; MESH: Animals; Listeriosis; Chemokine CCL4; MESH: Bacterial Proteins; MESH: Immunity; Chemokine CCL3; Leishmania major; MESH: Bystander Effect; MESH: Reactive Oxygen Species; MESH: Tumor Necrosis Factors; Articles; Macrophage Inflammatory Proteins; MESH: CD8-Positive T-Lymphocytes; 3. Good health; MESH: Chemokines, CC; Chemokines, CC; MESH: Immunologic Memory; MESH: Immunization; [SDV.IMM]Life Sciences [q-bio]/Immunology; Female; MESH: Listeria Infections; MESH: Mutation; MESH: Interferon Type II; MESH: Macrophage Inflammatory Proteins; MESH: Models, Immunological; Interferon-gamma; 03 medical and health sciences; Bacterial Proteins; Animals; MESH: Chemokine CCL3; MESH: Cytotoxicity, Immunologic; MESH: Chemokine CCL4; MESH: Mice; MESH: Time Factors; Immunity; Models, Immunological; Bystander Effect; Listeria monocytogenes; MESH: Tumor Necrosis Factor-alpha; Mutation; Immunization; MESH: Female; Immunologic Memory

Cytolysis, interferon γ and tumor necrosis factor (TNF) α secretion are major effector mechanisms of memory CD8+ T cells that are believed to be required for immunological protection in vivo. By using mutants of the intracellular bacterium Listeria monocytogenes, we found that none of these effector activities is sufficient to protect against secondary infection with wild-type (WT) bacteria. We demonstrated that CCL3 derived from reactivated memory CD8+ T cells is required for efficient killing of WT bacteria. CCL3 induces a rapid TNF-α secretion by innate inflammatory mononuclear phagocytic cells (MPCs), which further promotes the production of radical oxygen intermediates (ROIs) by both MPCs and neutrophils. ROI generation is the final bactericidal mechanism involved in L. monocytogenes clearance. These results therefore uncover two levels of regulation of the antibacterial secondary protective response: (a) an antigen-dependent phase in which memory CD8+ T cells are reactivated and control the activation of the innate immune system, and (b) an antigen-independent phase in which the MPCs coordinate innate immunity and promote the bactericidal effector activities. In this context, CCL3-secreting memory CD8+ T cells are able to mediate “bystander” killing of an unrelated pathogen upon antigen-specific reactivation, a mechanism that may be important for the design of therapeutic vaccines.