CCR2-dependent intraepithelial lymphocytes mediate inflammatory gut pathology during Toxoplasma gondii infection

Abstract

Mice of the C57BL/6 strain develop acute ileal inflammation after infection with the protozoan parasite Toxoplasma gondii. This pathology resembles many key features of human Crohn's disease, including a Th1 cytokine profile with high levels of interferon γ (IFN-γ), interleukin 12 (IL)-12, and tumor necrosis factor α (TNF)-α, presence of pathogenic CD4+ T cells, and infiltration of gut flora into inflammed tissue. Using CCR2−/− mice, we identify a role for this chemokine receptor in the pathogenesis of inflammatory pathology during T. gondii infection. Lack of chemokine (C–C motif) receptor 2 (CCR2) was associated with low levels of CD103+ T lymphocytes in the intraepithelial compartment, Peyer's patch, and lamina propria relative to wild-type animals. Adoptive transfer of wild-type, but not IFN-γ−/−, intraepithelial T lymphocytes converted CCR2 knockout mice from a resistant to susceptible phenotype with respect to parasite-triggered inflammatory gut pathology. These results for the first time show a role for intraepithelial T lymphocytes in pathogenesis of ileitis triggered by a microbial pathogen.