T cell responses to Listeria monocytogenes
Introduction
Listeria monocytogenes is a Gram-positive bacterium responsible for listeriosis, a foodborne infection characterized by systemic dissemination of ingested bacteria from the intestine into the blood stream and various organs [1]. L. monocytogenes is able to infect both phagocytic and non-phagocytic cells. A hallmark of L. monocytogenes infection of host cells is its ability to enter the cell cytosol by escaping from the hydrolytic phagosome. It does so by means of a pore-forming toxin, listeriolysin O (LLO) [2]. Once in the cytosol, through the actin nucleator ActA, L. monocytogenes is capable of cell-to-cell spread, thereby evading the extracellular milieu and thus escaping from the neutralizing effects of antibodies and complement [3]. As a result of its presence in the host cell cytosol, L. monocytogenes is a potent inducer of CD8 T cell responses [4]. In fact, when systemically administered into mice, L. monocytogenes induces a potent CD8 T cell response that results in complete clearance of infecting bacteria and the acquisition of life-long protective immunity. Thus, the mouse model of listeriosis has been instrumental for the understanding of many aspects of protective CD8 T cell responses against intracellular microorganisms. In addition, infection with L. monocytogenes also induces strong activation of CD4 T cell responses, the importance of which is just starting to be unraveled. Another advantage of the listeria model arises from the genetic manipulability of this microorganism and the detailed knowledge of L. monocytogenes pathogenesis 3., 5.. This has allowed investigators to generate mutant strains of L. monocytogenes that, although avirulent, maintain the capacity to induce potent and protective acquired immune responses [6].
In this review, we focus on the latest progress in our understanding of T cell responses to L. monocytogenes. First, we discuss several aspects of the innate immune response, how they influence the development of T cell responses and how T cells participate in some aspects of innate defense against L. monocytogenes. Second, we discuss the latest advances in our understanding of CD8 T cell responses to L. monocytogenes and review the exciting recent work on the contribution of CD4 T cells to the maintenance of strong memory CD8 T cell responses. Finally, we discuss the latest advances in vaccine development using attenuated strains of L. monocytogenes as antigen delivery vectors.
Section snippets
Innate immunity and L. monocytogenes infection
It has long been known that innate immunity to L. monocytogenes plays a crucial role in controlling the initial bacterial burden, allowing time for acquired immune responses to develop and confer sterilizing immunity [7]. Innate and acquired immunity were at one time considered independent branches of the immune response, with innate immune responses simply providing constitutive, non-specific defense. With the identification of Toll-like receptors (TLRs), it has become evident that innate
CD8 T cell responses to L. monocytogenes
CD8 T cell responses to L. monocytogenes are perhaps the most studied aspect of the immune response to this intracellular pathogen. On entering eukaryotic cells, L. monocytogenes invades the cytosol of the infected cell, where secreted bacterial proteins are processed for presentation by MHC class I molecules (both classical MHC class Ia and non-classical MHC class Ib) on the professional antigen presenting cell (APC) surface. A protective cytotoxic T lymphocyte (CTL) response is mounted
Role of CD4 T cells in anti-L. monocytogenes immunity
In addition to CD8 T cell responses, infection with L. monocytogenes results in the generation of robust CD4 T cell responses [38]. During the course of L. monocytogenes infection, CD4 T cells produce large amounts of Th1 cytokines that are thought to contribute to the clearance of L. monocytogenes [39]. Cross-presentation might be a significant route for the presentation of L. monocytogenes epitopes to CD4 T cells, as the LLO-mediated escape into the cytosol presumably limits the availability
L. monocytogenes as a vaccine delivery vector
L. monocytogenes possesses many attributes that would make it a good antigen delivery system for vaccine strategies aimed at the induction of CD8 T cell responses. The extensive knowledge of the immune response induced by this pathogen, the definition of its pathogenesis, and the generation of highly attenuated strains that retain the complete immunostimulatory potential of wild-type L. monocytogenes 6., 50., 51., have enabled significant progress in vaccine design. For example, recombinant
Conclusions
During the past few years, the murine model of listeriosis has contributed extensively to the understanding of the development of protective CD8 T cell responses. It is now known that CD4 T cell help is required during priming of CD8 T cells in order to generate a life-long protective memory response to L. monocytogenes infection. Future studies will surely enhance our knowledge of the requirements to generate a long lasting protective immune response, an essential feature of any effective
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
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