Immunosuppression during acute Trypanosoma cruzi infection: involvement of Ly6G (Gr1(+))CD11b(+ )immature myeloid suppressor cells.
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-gamma 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-gammaR(-/-) 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-gammaR(-/-) spleens. Purified immature Gr1(+)CD11b(+) cells produced NO and expressed iNOS upon IFN-gamma 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-gammaR(-/-) and iNOS(-/- )mice, confirming that Gr1(+)CD11b(+) cells were not involved in their down-regulation. In contrast, IL-5, tumor necrosis factor and IFN-gamma 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-gamma-dependent NO secretion by immature Ly-6G (Gr1)(+)CD11b(+ )myeloid cells.
D000208:Acute Disease; D000818:Animals; D000950:Antigens, Ly / Q000032:analysis*; D039481:CD11b Antigen / Q000032:analysis*; D014355:Chagas Disease / Q000276:immunology*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000037:antagonists & inhibitors; D013154:Spleen / Q000166:cytology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000950:Antigens, Ly; D039481:CD11b Antigen; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D009569:Nitric Oxide; D007371:Interferon-gamma