Evasion of CD8 T Cell Mediated Protective Immunity

The importance of CD8 T cells during L. monocytogenes infection is currently attributed to the cytosolic niche of the pathogen, allowing it to evade many aspects of immune surveillance. However, L. monocytogenes has also evolved mechanisms to allow it to avoid CD8 T cell-mediated immune responses. The ability of L. monocytogenes to spread intercellularly, from cell to cell, without encountering the extracellular milieu allows the bacteria to avoid perforin-mediated killing. The bacteria are also able to take advantage of the precision of the CD8 T cell immune response and avoid killing by nonspecific T cells.

In L. monocytogenes-immunized mice challenged with a second L. monocytogenes infection, memory CD8 T cells provide the majority of protection allowing for rapid clearance of bacteria from the mice. These cytolytic T cells have two main mechanisms for inducing death of target cells: (1) Fas-FasL interactions and (2) perforin-dependent cytolysis. In perforin-mediated killing, a CD8 T cell recognizes its target cell, resulting in the release of perforin and granzymes from intracellular stores, resulting in pore formation and apoptosis of the target cell (Harty et al. 2000). Mice deficient in perforin are not more susceptible to L. monocytogenes infection although they have slightly slower rates of clearance of bacteria from spleens but not livers (Kagi et al. 1994). However, perforin-deficient mice immunized with L. monocytogenes have a major defect in their ability to provide protective immunity upon re-challenge with the bacteria (Kagi et al. 1994). This protection defect can be partially overcome by increasing the number of perforin-deficient L. monocytogenes-specific T cells, suggesting that other effector mechanisms can moderately compensate for perforin-mediated cytolysis (Messingham et al. 2003).

Studies from our laboratory have shown that the ability of L. monocytogenes to evade perforin-mediated immunity is due to the capacity of the bacteria to spread intercellularly. Unlike wild-type L. monocytogenes, infection with bacteria deficient in ActA, which cannot spread cell to cell, is quickly controlled in immunized perforin-deficient mice (San Mateo et al. 2002). CD8 T cell cytolysis is critical for protective immunity to L. monocytogenes capable of cell-to-cell spread while protective immunity against spread-defective L. monocytogenes is largely independent of cytolysis. Thus, intercellular spread of L. monocytogenes allows for evasion of perforin-mediated cytolysis.

The intracellular niche of L. monocytogenes also allows the bacterium to avoid being killed by nonspecific CD8 T cell responses. Studies from our laboratory have shown that there is minimal killing of bystander bacteria by activated CD8 T cells in a recombinant L. monocytogenes system (Jiang et al. 2003). Mice were immunized with lymphocytic choriomeningitis virus (LCMV) to generate memory CD8 T cells and then challenged with a mixture of wild-type L. monocytogenes and recombinant L. monocytogenes expressing LCMV-derived antigen. Only the LCMV-antigen expressing strain was rapidly cleared by the memory CD8 T cells. The LCMV-immunized mice still had very high levels of wild-type L. monocytogenes in their spleens, comparable to levels found in infected unimmunized mice. The intracellular nature of L. monocytogenes may allow the bacteria to limit their exposure to the bystander killing by phagocytic cells that are activated by memory CD8 T cells. Thus, L. monocytogenes evades nonspecific CD8 T cell cytolysis, due in part to the inherent precision of the immune response.

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