Maizels, “Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo,” The

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-4GITRhigh, with a lesser fraction coexpressing CD25. Upon Ag stimulation, CD4CTLA-4GITRhigh 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 CD25GITR 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. The Journal of Immunology, 2005, 174: 4924–4933. F ilarial nematodes exert profound down-regulatory effectson the immune systems of their hosts. In seminal workover 20 years ago, the loss of Ag-specific T cell prolifer-ative responses in infected humans was reported (1, 2). Substantial work has since confirmed that immune depression is not confine