Fucosylated glycans of Taenia crassiceps polarize immune responses towards Th-1 type via toll like receptor [TLR] signaling and interferon-gamma production

ABSTRACT

The role of the macrophage vis-a-vis NK/T cells in determining the outcome of an immune response to a pathogen, whether Th-1 or Th-2, constitutes a fundamental issue in immunoregulation. Such knowledge is also of paramount importance in understanding the immunopathology of chronic human diseases like tuberculosis, leishmaniasis, hepatosplenic schistosomiasis, cysticercosis and neurocysticercosis. The conventional hypothesis states that interferon gamma [IFN-gamma] produced by T-cells and NK cells, in response to interleukin-12 [IL-12] from macrophages directs the immune response towards a Th-1 type, while IL-4, IL-5 and IL-10 result in a Th-2 type, upon antigen presentation with the necessary co-stimulatory molecules. In this report, we provide evidence that parasite glycans induce IFN-gamma and interleukin-6 [IL-6] production in na‹ve murine spleen cells, via toll like receptor [TLR] activation, possibly from macrophages. The IFN-gamma response is self-limiting. We propose that the relative balance of IFN-gamma and IL-6 determines the total immune response, whether Th-1, Th-1/Th-2 or Th-2 biased. Prolonged stimulation of macrophages by parasite glycans via TLRs down regulates the macrophage IFN-gamma response resulting an IL-6 dominated Th-2 environment. This is an adaptation by the parasite to down regulate the early parasite restrictive Th-1 response to a late parasite permissive Th-2 response during the course of infection. It is proposed that in parasitic helminth infections, the generation of either a Th-1 or a Th-2 response is determined at least in part at the macrophage level, prior to the involvement of NK/T cells and occurs when macrophages first encounter pathogen specific molecules via TLRs