Role of cytokines in the innate immune response to intracellular pathogens.

Abstract

Interplay between innate and adaptive immunity Intracellular pathogens live inside host cells, and survival is dependent on coexistence with the host. In their intracellular niche these pathogens are well shielded from the eVector cells of the cellular immune system. However, microbial proteins are processed and presented, thus promoting activation of T lymphocytes. These T lymphocytes determine resistance, susceptibility, and often immunopathogenesis of intracellular infections. Pathogenic intracellular bacteria and parasites include diVerent species of Listeria, Mycobacteria, Salmonella, Chlamydia, Rickettsia, Trypanosoma, and Leishmania. Although CD4+ lymphocytes are central to acquired resistance, an increasing amount of evidence is emerging showing crucial contributions by CD8+ T cells as well as unconventional T cells. These include CD4−, CD8− TCRáâ+ T cells recognising mycobacterial lipid antigens, T cells expressing the TCRãä or natural killer T cells, which are thought to have a regulatory function in the early immune response. Facultative intracellular microbes favour mononuclear phagocytes as their biotope, but can survive in the extracellular environment. In contrast, obligate intracellular bacteria such as Rickettsiae and Chlamydiae must enter host cells, because their metabolism requires nutrients of the eukaryotic cell. The diVerent types of immune response fall into two categories: innate immune response and adaptive immune responses (table 1). The major diVerence between innate and acquired immune responses is that the latter are highly specific for a particular pathogen. Moreover, although the innate immune response does not alter on repeated exposure to a given infectious agent, the adaptive response improves with each successive encounter with the same pathogen. Because innate immunity functions at times before adaptive immunity, its major role is likely to be to initiate defence early during primary infections. There is growing appreciation of the immunoregulatory role of the innate immune responses both in activating cellular constituents of innate immunity and in shaping downstream acquired responses. In addition to immediately activating eVector functions of the innate cellular constituents, natural killer cells and phagocytes (for example, macrophages, dendritic cells) secrete soluble mediators that can modify cell traYcking to attract eVector cells to sites of infections and concentrate T and B cells of the acquired immune system at sites of antigen presentation. The emerging picture is that in response to infection, immunocytes express a finely balanced and tightly regulated pattern of cytokines, which promote the most eVective immunity against the infecting agent. As a result, innate immunity functions not only to protect the host from infection while slower adaptive immune responses are developing, but also to direct the qualitative and quantitative nature of adaptive immunity. Growth of intracellular pathogens is restricted by several mechanisms acting in concert: (a) phagosome-lysosome fusion creates a hostile environment exposing the microbes to degrading lysosomal enzymes and a low pH; (b) macrophages restrict the availability of essential nutrients to the microbe—for example, the degradation of tryptophan has been associated with increased killing of Chlamydia psittaci and Toxoplasma gondii; (c) host cells produce highly reactive toxic molecules, particularly oxygen and nitrogen radicals, which are toxic for the microbe. The following considerations aim at outlining the decisive role of cytokines and eVector molecules which act early after microbial infection to shape a protective immune response. Firstly, the significance of cytokines in the innate immune response with focus on type I interferons (IFNá/â) will be highlighted using murine leishmaniasis as a model. Secondly, the diVerential induction of antibacterial activity against an important human pathogen, Mycobacterium tuberculosis, by cytokines and Toll-like receptors (TLR) will exemplify that the investigation of human cells is essential to gain detailed insight into the eVector mechanisms of innate immunity.

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Cite this paper

@article{Stenger2001RoleOC, title={Role of cytokines in the innate immune response to intracellular pathogens.}, author={Steffen Stenger and Martin Roellinghoff}, journal={Annals of the rheumatic diseases}, year={2001}, volume={60 Suppl 3}, pages={iii43-6} }