The role of cytokines in experimental listeriosis

Abstract

Listeria monocytogenes is a Gram-positive, intracytoplasmatically replicating pathogen that elicits host reactions which are very similar in man and rodents. Using murine listeriosis as a highly reproducible and convenient experimental model for studying the immune response to infections with facultative intracellular bacteria, Mackaness developed the concept of T cell-mediated macrophage activation as the pivotal mechanism in host defense against this type of infectious agents. Continued research in listeriosis itself, however, provided paradoxical findings that challenged the original dogma. In particular, the finding that T cell-mediated inflammatory events, like DTH and granuloma formation, can be dissociated from protective effector mechanisms has provided a new impetus and experimental access to characterizing the molecular mediators responsible for these diverging phenomena. This review first summarizes the cellular basis for the dichotomy of immunological phenomena outlined above and will then relate recent findings on cytokine expression in infected tissues to these dual categories of the host response to infection. The authors will focus on data obtained from in vivo experiments and draw on evidence from in vitro systems only when appropriate in vivo verification is still lacking. The data presented will cover the developments made in the field of cytokine research since our previous review in 1981 (Rev. Infect. Dis. 3: 1221-1250). Detectable numbers of listeria-specific T cells become apparent on day 4 to 5 of a primary infection. Whereas the localized and sustained release of TNF and IFN-gamma mediated by CD4+ cells seems to be the focusing event triggering mononuclear cell accumulation, the coincidental eradication of bacteria critically depends on CD8+ and/or CD4-CD8-Thy1+ cells. Their effector functions, however, remain obscure, since cytokines cannot be identified that will substitute for their presence. None of the cytokines studied thus far has been demonstrated to effectively cure an established infection. In addition, the increased production of cytokines characteristic of an anamnestic response (IL-2, IL-3, IL-4, IFN-gamma and TNF) can be dramatically reduced by depleting CD4+ T cells without any effect on the animal's ability to eradicate high lethal doses of bacteria and Listeria-specific CD8+ T cells can mediate protection even in the presence of neutralizing antibodies to IFN-gamma. In conclusion, the murine model of Listeria infection provides an interesting experimental approach for the development of immunotherapeutic strategies aimed at reducing T cell-mediated immunopathology without interfering with innate resistance and T cell-mediated cure and prevention of disease.