International Immunology, Vol. 14, No. 10, pp. 1125-1134,
October 2002
© 2002 Japanese Society for Immunology
FEATURED ARTICLE OF THE MONTH |
Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1+)CD11b+ immature myeloid suppressor cells
1 Centro de Biología Molecular (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain
Correspondence to: M. Fresno; E-mail: Mfresno{at}cbm.uam.es
Transmitting editor: C. Terhorst
Trypanosoma cruzi infection is associated with a severe unresponsiveness of spleen cells (SC) to antigens and mitogens. A high production of NO by concanavalin A (Con A)-stimulated SC from infected but not from control mice was observed. Neutralization of endogenous IFN-
production or treatment with NO synthase (NOS) inhibitor, L-N-monomethyl-arginine, blocked Con A-induced NO production and greatly restored proliferation by SC from infected mice. This was confirmed by using IFN-R–/– and inducible NOS (iNOS)–/– knockout mice, since unresponsiveness to mitogens of SC from those infected mice was much less pronounced than in control littermates. Interestingly, SC unresponsiveness was associated with a huge increase in CD11b+ cells that express Ly-6G (Gr1)+ and other immature myeloid markers These cells were absent in infected IFN-R–/– spleens. Purified immature Gr1+CD11b+ cells produced NO and expressed iNOS upon IFN- treatment, and were able to inhibit T cell proliferation. In addition, depletion of myeloid CD11b+ cells abrogated NO production and restored mitogen-induced proliferation, but not IL-2 synthesis, in SC from infected mice. IL-2 production and CD25 cell surface expression by mitogen-activated T cells were greatly depressed in SC from IFN-R–/– and iNOS–/– mice, confirming that Gr1+CD11b+ cells were not involved in their down-regulation. In contrast, IL-5, tumor necrosis factor and IFN- production, and CD69 expression by T cells were not depressed in infected SC. The results indicate the existence of an immunosuppressive mechanism during T. cruzi infection, mediated through IFN--dependent NO secretion by immature Ly-6G (Gr1)+CD11b+ myeloid cells.
Keywords: cytokines, nitric oxide, parasitic protozoan, suppression, T lymphocyte
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