cruziinfection [37] and induce IL-10 production

cruziinfection [37] and induce IL-10 production. mice, but not C3H/HeSnJ mice, had a high frequency of total IL-10-producing CD8+T cells and both CD4+and CD8+subsets of IFN+IL-10+double-producing T PBIT cells. Furthermore,T. cruziinfection of IL-10/C57BL/6J mice phenocopied fatal contamination in wild type C3H/HeSnJ mice with complete loss of parasite control. Adoptive transfer experiments indicated that T cells were a source of protective IL-10. Thus, in this system IL-10 production by T cells promotesT. cruzicontrol and protection from fatal acute myocarditis. Keywords:Parasitic-protozoan, cytokines, T cells, inflammation == Introduction == Chagas Disease is usually a vector-borne zoonosis restricted to Latin America caused by contamination with the protozoanTrypanosoma cruzi. The prevalence of Chagas Disease remains high, approximately 10 million in the year 2006 according to estimates by the World Health Business [1], in part due to inadequate implementation of vector and blood supply control programs. Currently, there is no vaccine available and the few approved drugs are of limited use PBIT due to serious side-effects and limited efficacy [2]. Risk factors and immunopathogenic mechanisms inT. cruziinfection are poorly understood. The acute phase is usually short and subclinical, but over time ~20-30% of patients progress to clinically evident Chagas Disease, mainly manifest as dilated cardiomyopathy [3]. Consistent with the intracellular way of life ofT. cruzi, studies in animal models and with human subjects strongly suggest that it induces a Th1-polarized immune-mediated process in affected organs [4]. Mice genetically deficient in the signature Th1 cytokines IL-12 or IFN, the IFNinduced effector enzyme iNOS [5], the Th1-associated chemokine receptors CCR2 [6] or CCR5 [7], and the Th1-associated ligands for chemokine receptor CXCR3 [8] all develop increased parasitism after contamination,and some have high Rabbit Polyclonal to ATG16L2 acute mortality. Persistent parasitism and type 1 responses may promote progression to the chronic phase. In animal models of chronic contamination, parasite DNA and antigens are still found in infected tissues in the presence of cell infiltration and fibrosis, indicating an inappropriate or ineffective immune response. In chronic humanT. cruziinfection, the cytokine profile in the heart is also Th1-polarized [9], and PBMCs produce high levels of IFN and low levels of IL-10 [10]. A problem in interpreting results from mouse models ofT. cruziinfection is usually that many different models have been used with many different parasite strains and inocula and diverse PBIT mouse strains, with variable outcomes from the many labs working in the field. In the present study, we have systematically and directly compared the clinical, parasitologic, pathologic, immunologic and molecular correlates of contamination using the myotropic Colombiana strain ofT. cruzi[11] in two experimental mouse models with opposite outcomes: C57BL/6J, which control parasitism and survive contamination, and C3H/HeSnJ, which fail to control parasitism and die. This approach allowed us to identify a strong association of IL-10 and IL-10-producing cells with resistance and to test the functional importance of IL-10 directly using gene knockout mice and adoptive transfer experiments. This confirms previous reports of IL-10 as a protective factor inT. cruziinfection [12-15] and provides new insights with regard to the source of IL-10 and its effects on parasitism. == Materials and Methods == == Animals and Parasite == The following mice were obtained from Jackson Laboratory (Bar Harbor, ME): Wild type male C57BL/6J mice (stock number 664); wild type male C3H/HeSnJ mice (stock number 661); IL-10 deficient male mice (stock number 2251, backcrossed for 10 generations onto the C57BL/6J background); RAG-1 deficient male mice (stock number 2216, backcrossed for 10 generations onto the C57BL/6J background); C3.SW-H2b/SnJ male mice (stock number 0438); and C3H/HeJ male mice (stock number 659). Inbred wild type male C3H/HeN mice and wild type male C57BL/6N mice were obtained from Taconic Farms (Hudson, NY). Parasitemia and mortality were comparable afterT. cruziinfection of the C57BL/6 and C3H/He lines obtained from Jackson and from Taconic Farms (not shown). Mice were infected at 8-10 wks of age and housed in cages under specific.