Vaccination with Irradiated Listeria Induces Protective T Cell Immunity

Abstract

We evaluated gamma-irradiated Listeria monocytogenes as a killed bacterial vaccine, testing the hypothesis that irradiation preserves antigenic and adjuvant structures destroyed by traditional heat or chemical inactivation. Irradiated Listeria monocytogenes (LM), unlike heat-killed LM, efficiently activated dendritic cells via Toll-like receptors and induced protective T cell responses in mice. Like live LM, irradiated LM induced Toll-like-receptor-independent T cell priming. Cross-presentation of irradiated listerial antigens to CD8(+) T cells involved TAP- and proteasome-dependent cytosolic antigen processing. These results establish that killed LM can induce protective T cell responses, previously thought to require live infection. gamma-irradiation may be potentially applied to numerous bacterial vaccine candidates, and irradiated bacteria could serve as a vaccine platform for recombinant antigens derived from other pathogens, allergens, or tumors.

Nondividing but Metabolically Active Gamma-IrradiatedBrucella melitensisIs Protective against VirulentB. melitensisChallenge in Mice

“…It is noteworthy that irradiated Brucella demonstrated enhanced protection compared to metabolically inactive heat-treated bacteria. Our results are consistent with previous reports using gamma-irradiated B. abortus strain RB51 and gamma-irradiated Listeria monocytogenes (13,38) Importantly, different approaches generating nonreplicating metabolically active organisms result in effective protection against intracellular pathogens (8,13,23,38). Together, these findings suggest that despite the inactivation method, metabolic activity is the key component mediating effective immunity.…”

“…In addition, metabolism and protein secretion are known to be important components in triggering host T cells, since secreted bacterial proteins are more efficient in eliciting protective T cells than nonsecreted antigens (10,37,47). Moreover, vaccination against intracellular L. monocytogenes with a metabolically active but replication-incompetent vector induces protective Tcell immunity (8,13).…”

KBMA Listeria monocytogenes is an effective vector for DC-mediated induction of antitumor immunity

“…The very limited number of crosslinks, however, preserves their metabolic activity, ability to exit the phagolysosome, and ability to escape into the cytosol. L. monocytogenes that are inactivated by high doses of S-59, with a correspondingly increased number of cross-links per genome, have abrogated replication and metabolic activity, similar to the recently described L. monocytogenes inactivated by irradiation (38).…”

“…Immunization of mice with a mixture of live and HK L. monocytogenes does not alter the phenotype of the CD8 + T cells primed by the HK L. monocytogenes, thus the absence of an inflammatory milieu cannot alone explain this intrinsic difference (26). Several approaches have been utilized to interfere with the replication of L. monocytogenes while preserving T cell-stimulatory capacity (38,39). For clinical application, a well-controlled, cost-effective method with consistent inactivation of L. monocytogenes and full DC-stimulatory potential is preferred.…”

Mucosal adjuvant activity of cholera toxin requires Th17 cells and protects against inhalation anthrax

“…Mouse bone-marrow cells were cultured for 6 d with GM-CSF (BD Biosciences) to obtain myeloid DCs (15). The DCs were incubated with OVA and indicated stimuli.…”