Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo.

Taylor, Matthew D; LeGoff, Laetitia; Harris, Anjanette; Malone, Eva M; Allen, Judith E; Maizels, Rick M

Abstract

Human filarial parasites cause chronic infection associated with long-term down-regulation of the host’s immune response. We show here that CD4+ T cell regulation is the main determinant of parasite survival. In a laboratory model of infection, using Litomosoides sigmodontis in BALB/c mice, parasites establish for >60 days in the thoracic cavity. During infection, CD4+ T cells at this site express increasing levels of CD25, CTLA-4, and glucocorticoid-induced TNF receptor family-related gene (GITR), and by day 60, up to 70% are CTLA-4+GITRhigh, with a lesser fraction coexpressing CD25. Upon Ag stimulation, CD4+CTLA-4+GITRhigh cells are hyporesponsive for proliferation and cytokine production. To test the hypothesis that regulatory T cell activity maintains hyporesponsiveness and prolongs infection, we treated mice with Abs to CD25 and GITR. Combined Ab treatment was able to overcome an established infection, resulting in a 73% reduction in parasite numbers (p < 0.01). Parasite killing was accompanied by increased Ag-specific immune responses and markedly reduced levels of CTLA-4 expression. The action of the CD25+GITR+ cells was IL-10 independent as in vivo neutralization of IL-10R did not restore the ability of the immune system to kill parasites. These data suggest that regulatory T cells act, in an IL-10-independent manner, to suppress host immunity to filariasis.

Citation

Taylor, M. D., LeGoff, L., Harris, A., Malone, E. M., Allen, J. E., & Maizels, R. M. (2005). Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo. Journal of Immunology, 174, 4924-4933

• Journal Article Type: Article
• Publication Date: Apr 15, 2005
• Deposit Date: Jul 2, 2008
• Print ISSN: 0022-1767
• Electronic ISSN: 1550-6606
• Publisher: American Association of Immunologists
• Peer Reviewed: Peer Reviewed
• Volume: 174
• Pages: 4924-4933
• Keywords: filarial; parasites; chronic infection; immunity; regulatory T cells
• Public URL: http://researchrepository.napier.ac.uk/id/eprint/1668