DESCRIPTION (provided by applicant): Adjuvants are critical molecules involved in driving protective immune responses in vivo. They exhibit strong proinflammatory effects, are often derived from pathogens -in such case they are defined as pathogens associated molecular patterns (PAMPs)- and possess all features of danger molecules. They are detected as such by the immune system that has evolved a set of immune receptors, the pattern recognition receptors (PRRs), which recognize them. While enormous advances have been made in characterizing multiple adjuvants over the past decade, the molecular mechanisms of their precise effects are still the subject of intense studies. Adjuvant recognition by immune cells leads to a set of critical events that are necessary for optimal T cell priming and differentiation into effector and memory cells. CD8+ T cells which represent a crucial effector arm of the adaptive immune response require such signals for their optimal activation. In fact, the development of a protective immune response against several pathogenic organisms and diseases is dependent on the ability of antigen-specific CD8+ T cells to best differentiate. These cells confer immunity via the expression of various effector mechanisms such as cytolysis of infected cells and release of proinflammatory cytokines and chemokines that recruit and activate innate immune effector cells. The molecular factors that orchestrate CD8+ T cell differentiation are still incompletely defined and depending on the initial stimuli, the outcome of the priming and the functional features of the T cells are different. Adjuvants in fact represent key mediators of such modulation and therefore can orchestrate adaptive immune responses. Mice immunized with the intracellular bacterium Listeria monocytogenes (Lm) develop life-long immunity against a challenge infection by Lm. Using this model system, we established that secretion of the proinflammatory chemokine CCL3 / MIP-1a (Macrophage Inflammatory Protein 1a) by memory CD8+ T cells early during secondary challenge infection is critical for protective immunity either against the same or a distinct (bystander immunity) intracellular pathogen. Recently we found that amongst memory CD8+ T cells, the CCL3+ cells which represent a substantial proportion (~30%) concomitantly express several effector functions such as granzyme B, perforin, IL-2, IFN-g, TNF-a suggesting that they represent multifunctional memory cells. Our current data also suggest that induction of these cells is likely to depend on one bacterial protein, the p60 autolysin, a virulence factor of the bacteria, which functions to digest peptidoglycan (PGN) cell walls. Our working hypothesis proposes that p60 is orchestrating the induction of CCL3+ plurifunctional memory CD8+ T cells which are important for long-term protective immunological memory. The current project will therefore (i) define the function of the Lm-derived p60 protein that controls the induction of protective CD8 memory and (ii) define the intracellular pathways and inflammatory signals triggered by the p60 protein.
|Effective start/end date||2/15/12 → 1/31/14|
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