BACKGROUND & AIMS: Toxoplasma gondii, an obligate intracellular parasite, can invade intestinal epithelial cells and elicit a robust Th1 immune response. In this model of intestinal inflammation, CD8(+) intraepithelial lymphocytes (IELs) secrete transforming growth factor (TGF)-beta, which appears necessary for the maintenance of homeostasis in the intestine. However, the mechanism responsible for the IEL migration to the inflamed intestine is still unclear. METHODS: An in vitro coculture cell system was used to quantify the IEL attraction by an infected intestinal epithelial cell line (m-IC(cl2)). We used CCR5-deficient mice to determine which chemokine receptor-chemokine interaction could be responsible for the recruitment of antigen-specific CD8(+) IELs to the small intestine for the promotion of parasite clearance and host recovery. RESULTS: We observed increased expression of several chemokine receptors (CCR1, CCR2, CCR5, CXCR3) in the infected ileum. In particular, CCR5 expression was markedly increased in antigen-primed CD8(+) IELs. Experiments using recombinant chemokines as well as blocking antibodies showed that macrophage inflammatory protein (MIP)-1alpha and MIP-1beta were critical for their homing. CD8(+) IELs isolated from CCR5-deficient mice (CCR5-/-), despite their high production of TGF-beta and overexpression of activation markers, were impaired in their ability to migrate in vitro to the m-IC(cl2) monolayer or in vivo to the inflamed intestine after adoptive transfer. CONCLUSIONS: Our data emphasize the biologic role of CCR5 as an important component in the migration of intraepithelial CD8(+) T cells and the regulation of the inflammatory response following parasite infection.
BACKGROUND & AIMS: Toxoplasma gondii, an obligate intracellular parasite, can invade intestinal epithelial cells and elicit a robust Th1 immune response. In this model of intestinal inflammation, CD8(+) intraepithelial lymphocytes (IELs) secrete transforming growth factor (TGF)-beta, which appears necessary for the maintenance of homeostasis in the intestine. However, the mechanism responsible for the IEL migration to the inflamed intestine is still unclear. METHODS: An in vitro coculture cell system was used to quantify the IEL attraction by an infected intestinal epithelial cell line (m-IC(cl2)). We used CCR5-deficient mice to determine which chemokine receptor-chemokine interaction could be responsible for the recruitment of antigen-specific CD8(+) IELs to the small intestine for the promotion of parasite clearance and host recovery. RESULTS: We observed increased expression of several chemokine receptors (CCR1, CCR2, CCR5, CXCR3) in the infected ileum. In particular, CCR5 expression was markedly increased in antigen-primed CD8(+) IELs. Experiments using recombinant chemokines as well as blocking antibodies showed that macrophage inflammatory protein (MIP)-1alpha and MIP-1beta were critical for their homing. CD8(+) IELs isolated from CCR5-deficient mice (CCR5-/-), despite their high production of TGF-beta and overexpression of activation markers, were impaired in their ability to migrate in vitro to the m-IC(cl2) monolayer or in vivo to the inflamed intestine after adoptive transfer. CONCLUSIONS: Our data emphasize the biologic role of CCR5 as an important component in the migration of intraepithelial CD8(+) T cells and the regulation of the inflammatory response following parasite infection.
Authors: Débora M G Sant'Ana; Marcelo B Góis; Jacqueline N Zanoni; Aristeu V da Silva; Cleverton J T da Silva; Eduardo J A Araújo Journal: Int J Exp Pathol Date: 2012-08 Impact factor: 1.925
Authors: David C Soler; Hideaki Sugiyama; Andrew B Young; Jessica V Massari; Thomas S McCormick; Kevin D Cooper Journal: Clin Immunol Date: 2013-07-06 Impact factor: 3.969
Authors: Allison L Bierly; William J Shufesky; Woraporn Sukhumavasi; Adrian E Morelli; Eric Y Denkers Journal: J Immunol Date: 2008-12-15 Impact factor: 5.422