Memory CD8+ T cells mediate antibacterial immunity via CCL3 activation of TNF/ROI+ phagocytes.
Cytolysis, interferon gamma and tumor necrosis factor (TNF) alpha 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-alpha 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.
Narni-Mancinelli
Emilie
E
Institut National de la Santé et de la Recherche Médicale E-344, Groupe Avenir, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France.
Campisi
Laura
L
Bassand
Delphine
D
Cazareth
Julie
J
Gounon
Pierre
P
Glaichenhaus
Nicolas
N
Lauvau
Grégoire
G
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D024201:Bystander Effect / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000469:parasitology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D007109:Immunity / Q000276:immunology*; D007114:Immunization; D007156:Immunologic Memory / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018448:Models, Immunological; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology* / Q000382:microbiology; D017382:Reactive Oxygen Species; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000276:immunology*
D001426:Bacterial Proteins; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma
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