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Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis¹

Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

African trypanosomes are single-cell, extra-cellular blood parasites causing profound immunosuppression. Susceptible BALB/c mice infected s.c. into a footpad with 10⁴ Trypanosoma congolense die with fulminating parasitemia within 10 days. We injected BALB/c mice 2 days before such an infection with different doses of a depleting mAb specific for CD25, a surface marker of regulatory T cells (Tregs). Pretreatment with a low, optimal dose of anti-CD25 resulted in a dramatic effect, in that the infected mice did not develop parasitemia, as well as eliminated all parasites and showed no signs of disease. Their spleens showed a 100% reduction of CD4⁺CD25^high T cells and overall a 70% reduction of CD4⁺CD25⁺Foxp3⁺ T cells 7 days postinfection. The protective effect of treatment with an optimal dose of anti-CD25 could be reversed by administration of L-N6-(1-imminoethyl) lysine, a specific inhibitor of inducible NO synthase or administration of anti-CD8 Ab. Analysis of the cytokine patterns and cell surface marker in infected mice pretreated with anti-CD25 Abs pointed to a potential NKT cell response. We then conducted infections in CD1d^–/– mice. From our observations, we conclude that CD4⁺CD25^highFoxp3⁺ Tregs prevent, in normal infected susceptible mice, an early protective response mediated by CD8⁺ NKT cell-dependent activation of macrophages to kill parasites by production of NO. Our results also indicate that different populations of NKT cells have protective or suppressive effects. Our observations lead us to propose a hypothesis of cross-regulation of NKT cells and Tregs in trypanosome infections.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by the Canadian Health Research Institute/Regional Partnership Program.

² Address correspondence and reprint requests to Dr. Henry Tabel, Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B4, Canada. E-mail address: henry.tabel{at}usask.ca

³ Abbreviations used in this paper: VSG, variant surface glycoprotein; i.f.p., into a foot pad; L-NIL, L-N6-(1-imminoethyl) lysine; Treg, regulatory T cell; wt, wild type.