Journal
GASTROENTEROLOGY
Volume 125, Issue 2, Pages 491-500Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/S0016-5085(03)00903-X
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Funding
- FIC NIH HHS [TW01003] Funding Source: Medline
- NIAID NIH HHS [R01 AI019613] Funding Source: Medline
- PHS HHS [A130000, A119613] Funding Source: Medline
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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-ICcl2). 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-ICcl2 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.
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