DIFFERENTIAL INDUCTION, MAINTENANCE AND REGULATION OF CD8<+> T CELL RESPONSE AGAINST A MODEL ANTIGEN EXPRESSED BY AN ACUTE VERSUS A CHRONIC INTRACELLULAR BACTERIUM

The invention disclosed relates to CD8 T cell response against a model antigen, Ovalbumin (Ova257-264) expressed by Listeria monocytogenes (LM, inducing an acute infection, 150 days). Lower doses of both pathogens induced stronger bacterial growth but weaker T cell memory indicating that memory correlates with pathogen dose but not with bacterial expansion. LM-Ova induced a rapid effector response followed by a rapid, but massive attrition. BCG-Ova on the other hand, induced a slower, but chronic, effector response followed by a gradual decline thereafter. CD8 T cell response induced by BCG-Ova was highly dependent on pathogen-persistence as removal of BCG-Ova by antibiotics compromised CD8 T cell frequency suggesting that persistence of antigen is important for protective CD8 T cell memory. In spite of a stronger initial T cell response with LM-Ova, BCG-Ova provided more effective tumor (B16Ova) control at both local and distal sites due to the induction of a persistently activated acquired and a more potent innate immunity. Thus, the state of memory CD8 T cells rather than the number of memory CD8 T cells is important for tumor control and expression of tumor antigens in BCG represents an ideal strategy for ensuring the maintenance of memory CD8 T cells in a persistently activated state. Additionally, the expression of anti-apoptotic and memory promoting cytokine IL-15 by BCG results in continuous IL-15 expression in vivo and further enhancement of CD8 T cell memory. L'invention concerne la réponse des lymphocytes T CD8 contre un antigène modèle, Ovalbumine (Ova257-264), exprimé par Listeria monocytogenes (LM, induisant une infection aiguë, 150 jours). Des doses inférieures des deux agents pathogènes induisent une croissance bactérienne plus forte, mais également une mémoire des lymphocytes T plus faible, ce qui indique que la mémoire établit une corrélation avec une dose d'agent pathogène mais pas avec une expansion bactérienne. LM-Ova induit une réponse d'effecteur rapide, suivie d'une attrition rapide mais massive. BCG-Ova, quant à lui, induit une réponse d'effecteur plus lente, mais chronique, suivie d'un déclin graduel. La réponse des lymphocytes T CD8 induite par BCG-Ova est hautement dépendante de la persistance des agents pathogènes. L'élimination de BCG-Ova par des an