Source: http://www.asmscience.org/content/book/10.1128/9781555816872.ch35
Timestamp: 2019-04-20 03:08:28+00:00

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This chapter focuses on three protozoan parasites: malaria, Leishmania, and Trypanosoma cruzi, that have in common their transmission by insect vectors, their intracellular lifestyle in the mammalian host, and the requirement for Th1 responses to control these infections. It discusses the mechanisms used by these parasites to actively suppress the development and/or expression of cell-mediated immunity that contribute to the state of equilibrium that is established between the host and the parasite in sites of chronic infection. The chapter describes the manner in which protozoan pathogens have learned to condition their initial encounter with dendritic cells (DCs) as a means to suppress or delay the onset of the adaptive response. Infection with T. cruzi parasites typically produces an acute blood and tissue parasitemia that is controlled, followed by long-term persistence of low numbers of parasites in muscle and nerve tissue, leading to chronic inflammation in these tissues and the formation of Chagas’ disease. In leishmaniasis, there has been a concerted effort to understand the immunologic defects controlling both the delayed onset of acquired resistance and the long-term persistence of organisms in the immune host following clinical cure. The chapter talks about a number of regulatory T-cell populations that have in common their ability to suppress the generation and function of effector T cells. For T. cruzi, its ability to infect any nucleated cell type and to subsequently escape from endocytic vacuoles, allows it to persist in cell types and in an intracellular compartment that minimizes exposure to the toxic metabolites of activated cells.
Subsets of regulatory and IL-10 producing T cells implicated in the suppression of immune responses to protozoan pathogens. nTregs undergo selection in the thymus for relatively high affinity recognition of self-peptide/MHC (major histocompatibility complexes). Their expansion in response to parasitic infection can be due to parasite antigens bearing cross-reactive epitopes with the self, or to activation of self-reactive clones in inflammatory sites rich in IL-2 and activated DCs. In most experimental and clinical studies in which the expansion of Foxp3+ Treg cells have been described, it is not possible to distinguish their origin from iTregs, which are generated following an encounter of conventional T cells with antigen in the periphery and in response to high levels of TGF-β. The presence of iTregs in patients with malaria is inferred from antigen specificity and correlation with elevated serum concentrations of TGF-β. Tr1 cells are peripherally differentiated IL-10+Foxp3–CD4+ T cells generated in response to antigen presented by regulatory DCs, which typically express subimmunogenic levels of antigen-MHC and costimulatory molecules, and secrete IL-10. IL-10 Th1 cells are T-bet+IFN-γ+ effector cells that simultaneously secrete IL-10. Their development can be driven by high dose or persistent antigen and IL-12 or IL-27.
Negative feedback loop initiated by protozoan pathogens inducing strong Th1 responses. TLR agonists and other stimulatory molecules delivered to DCs by malaria-infected RBCs (red blood cells), T. cruzi trypomastigotes or Leishmania amastigotes, during the acute stage of infection, activate Th1 effector cells that, under the influence of persistent, high dose antigen and instruction by IL-12 or IL-27, will comprise a population of cells that are transiently activated to coexpress IL-10. The IL-10 from Th1 cells will down regulate APC (antigen-presenting cell) function and, in conjunction with reduced antigen available for processing during the immune clearance phase, will establish conditions suitable for the predominance of a regulatory DC phenotype and activation of Tr1 cells that help to limit the effector response during the chronic stage of infection.
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