T Lymphocyte-Dependent IL-10 Protects Against a Lethal IL-12 Driven Cytokine Storm Initiated by Toxoplasma gondii GRA24

A model organism in the study of immunity to infection, Toxoplasma gondii has been instrumental in establishing many key principles of host anti-microbial defense and its regulation. Here, we employed an attenuated uracil auxotroph strain of Type I Toxoplasma designated OMP to further untangle the early immune response to this parasitic pathogen. Experiments using T cell-deficient TCRβ^-/- mice unexpectedly revealed that an intact αβ T lymphocyte compartment was essential to survive infection with this uracil auxotroph. Subsequent antibody depletion and knockout mouse experiments demonstrated contributions from CD4⁺ T cells and most predominantly CD8⁺ T cells in resistance to OMP. Using transgenic knockout mice, we found only a partial requirement for IFN-γ, and a lack of requirement for Toll-like receptor (TLR) adaptor MyD88 in resistance. In stark contrast to other studies on Toxoplasma, resistance to OMP did not require IL-12p40. Surprisingly, given the attenuated nature of OMP, T cell-dependent IL-10 was found to be critical for survival and deficiency of this cytokine triggered an abnormally high systemic inflammatory response. We also found that parasite molecule GRA24, a dense granule protein that triggers TLR-independent IL-12 production, acts as a virulence factor contributing to death of OMP-infected TCRβ^-/- mice. Further, resistance against OMP was restored in TCRβ^-/- mice via monoclonal depletion of IL-12p40, suggesting that GRA24-induced IL-12 underlies the fatal immunopathology observed. Collectively, our studies provide insight into a novel and rapidly arising T lymphocyte-dependent anti-inflammatory response to T. gondii which operates independently of MyD88 and IL-12, and that provides protection against the proinflammatory effects of GRA24.