TLR11-independent inflammasome activation is critical for CD4+ T cell-derived IFN-γ production and host resistance to Toxoplasma gondii

PLoS Pathog. 2019 Jun 13;15(6):e1007872. doi: 10.1371/journal.ppat.1007872. eCollection 2019 Jun.

Abstract

Innate recognition of invading intracellular pathogens is essential for regulating robust and rapid CD4+ T cell effector function, which is critical for host-mediated immunity. The intracellular apicomplexan parasite, Toxoplasma gondii, is capable of infecting almost any nucleated cell of warm-blooded animals, including humans, and establishing tissue cysts that persist throughout the lifetime of the host. Recognition of T. gondii by TLRs is essential for robust IL-12 and IFN-γ production, two major cytokines involved in host resistance to the parasite. In the murine model of infection, robust IL-12 and IFN-γ production have been largely attributed to T. gondii profilin recognition by the TLR11 and TLR12 heterodimer complex, resulting in Myd88-dependent IL-12 production. However, TLR11 or TLR12 deficiency failed to recapitulate the acute susceptibility to T. gondii infection seen in Myd88-/- mice. T. gondii triggers inflammasome activation in a caspase-1-dependent manner resulting in cytokine release; however, it remains undetermined if parasite-mediated inflammasome activation impacts IFN-γ production and host resistance to the parasite. Using mice which lack different inflammasome components, we observed that the inflammasome played a limited role in host resistance when TLR11 remained functional. Strikingly, in the absence of TLR11, caspase-1 and -11 played a significant role for robust CD4+ TH1-derived IFN-γ responses and host survival. Moreover, we demonstrated that in the absence of TLR11, production of the caspase-1-dependent cytokine IL-18 was sufficient and necessary for CD4+ T cell-derived IFN-γ responses. Mechanistically, we established that T. gondii-mediated activation of the inflammasome and IL-18 were critical to maintain robust CD4+ TH1 IFN-γ responses during parasite infection in the absence of TLR11.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / parasitology
  • CD4-Positive T-Lymphocytes / pathology
  • Caspase 1 / genetics
  • Caspase 1 / immunology
  • Caspases / genetics
  • Caspases / immunology
  • Caspases, Initiator
  • Immunity, Innate*
  • Inflammasomes / genetics
  • Inflammasomes / immunology*
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Interleukin-18 / genetics
  • Interleukin-18 / immunology
  • Mice
  • Mice, Knockout
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology*
  • Toxoplasma / immunology*
  • Toxoplasmosis, Animal / genetics
  • Toxoplasmosis, Animal / immunology*
  • Toxoplasmosis, Animal / pathology

Substances

  • IFNG protein, mouse
  • Inflammasomes
  • Interleukin-18
  • Tlr11 protein, mouse
  • Tlr12 protein, mouse
  • Toll-Like Receptors
  • Interferon-gamma
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Casp1 protein, mouse
  • Caspase 1