Dataset Information

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 gamma (IFN-gamma), interleukin 12 (IL)-12, and tumor necrosis factor alpha (TNF)-alpha, 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-gamma(-/-), 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.

SUBMITTER: Egan CE

PROVIDER: S-EPMC2860785 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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

Egan C E CE Craven M D MD Leng J J Mack M M Simpson K W KW Denkers E Y EY

Mucosal immunology 20090909 6

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 gamma (IFN-gamma), interleukin 12 (IL)-12, and tumor necrosis factor alpha (TNF)-alpha, presence of pathogenic CD4(+) T cells, and infiltration of gut flora into inflammed tissue. Using CCR2(-/-) mice, we identify a role for this chemokine rece ...[more]

PMID: 19741601

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Project description:Intraepithelial T lymphocytes (T-IELs), which constitute over 50% of the total T lymphocytes in the animal, patrol the mucosal epithelial lining to defend against pathogen invasion while maintaining gut homeostasis. In addition to expressing T cell markers such as CD4 and CD8, T-IELs display T cell receptors (TCR), including either TCRαβ or TCRγδ. Both humans and mice share similar T-IEL subsets: TCRγδ+, TCRαβ+CD8αα+, TCRαβ+CD4+, and TCRαβ+CD8αβ+. Among these subsets, human T-IELs are predominantly TCRαβ+ (over 80%), whereas those in mice are mostly TCRγδ+ (~60%). Of note, the majority of the TCRγδ+ subset expresses CD8αα in both species. Although T-IELs have been extensively studied in humans and mice, their profiles in cattle have not been well examined. Our study is the first to characterize bovine T-IELs using flow cytometry, where we identified several distinct features. The percentage of TCRγδ+ was comparable to that of TCRαβ+ T-IELs (both ~50% of CD3+), and the majority of bovine TCRγδ+ T-IELs did not express CD8 (CD8-) (above 60%). Furthermore, about 20% of TCRαβ+ T-IELs were CD4+CD8αβ+, and the remaining TCRαβ+ T-IELs were evenly distributed between CD4+ and CD8αβ+ (~40% of TCRαβ+ T-IELs each) with no TCRαβ+CD8αα+ identified. Despite these unique properties, bovine T-IELs, similar to those in humans and mice, expressed a high level of CD69, an activation and tissue-retention marker, and a low level of CD62L, a lymphoid adhesion marker. Moreover, bovine T-IELs produced low levels of inflammatory cytokines such as IFNγ and IL17A, and secreted small amounts of the immune regulatory cytokine TGFβ1. Hence, bovine T-IELs' composition largely differs from that of human and mouse, with the dominance of the CD8- population among TCRγδ+ T-IELs, the substantial presence of TCRαβ+CD4+CD8αβ+ cells, and the absence of TCRαβ+CD8αα+ T-IELs. These results provide the groundwork for conducting future studies to examine how bovine T-IELs respond to intestinal pathogens and maintain the integrity of the gut epithelial barrier in animals.

Dataset Information

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

Publications

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

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