The Journal of Experimental Medicine
StemCell Technologies
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Published online August 13, 2007
doi:10.1084/jem.20070204
The Journal of Experimental Medicine, Vol. 204, No. 9, 2075-2087
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Narni-Mancinelli et al.
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ARTICLE

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

Emilie Narni-Mancinelli1,2, Laura Campisi1,2, Delphine Bassand1,2, Julie Cazareth2,3, Pierre Gounon2, Nicolas Glaichenhaus1,2, and Grégoire Lauvau1,2

1 Institut National de la Santé et de la Recherche Médicale E-344, Groupe Avenir, Institut de Pharmacologie Moléculaire et Cellulaire, 06560 Valbonne, France
2 Université de Nice-Sophia Antipolis, UFR Sciences, 06108 Nice, France
3 Centre National de la Recherche Scientifique, UMR6097, 06560 Valbonne, France

CORRESPONDENCE Grégoire Lauvau: gregoire.lauvau{at}unice.fr

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.

Abbreviations used: HKLM, heat-killed Listeria monocytogenes; iNOS, inducible nitric oxide synthase; lys-M, lysozyme M; MPC, mononuclear phagocytic cell; RNI, reactive nitric intermediate; ROI, reactive oxygen intermediate; TEM, effector–memory; Tip-DC, TNF-{alpha}/iNOS-producing DC; TP-MPC, TNF-{alpha}–producing MPC.


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