CD4+T Cell Hyporesponsiveness after Repeated Exposure to Schistosoma mansoni Larvae Is Dependent upon Interleukin-10
The effect that multiple percutaneous exposures toSchistosomalarvae has on the development of early CD4+lymphocyte reactivity is unclear, yet it is important in the context of humans living in areas where schistosomiasis is endemic. In a murine model of multiple infections, we show that exposure of mice to repeated doses (4×) ofSchistosoma mansonicercariae, compared to a single dose (1×), results in CD4+T cell hyporesponsiveness within the skin-draining lymph nodes (sdLN), manifested as reduced CD4+cell proliferation and cytokine production. FoxP3+CD4+regulatory T cells were present in similar numbers in the sdLN of 4× and 1× mice and thus are unlikely to have a role in effecting hyporesponsiveness. Moreover, anergy of the CD4+cell population from 4× mice was slight, as proliferation was only partly circumvented through thein vitroaddition of exogenous interleukin-2 (IL-2), and thein vivoblockade of the regulatory molecule PD1 had a minimal effect on restoring responsiveness. In contrast, IL-10 was observed to be critical in mediating hyporesponsiveness, as CD4+cells from the sdLN of 4× mice deficient for IL-10 were readily able to proliferate, unlike those from 4× wild-type cohorts. CD4+cells from the sdLN of 4× mice exhibited higher levels of apoptosis and cell death, but in the absence of IL-10, there was significantly less cell death. Combined, our data show that IL-10 is a key factor in the development of CD4+T cell hyporesponsiveness after repeated parasite exposure involving CD4+cell apoptosis.