CD4+ T cell hyporesponsiveness after repeated exposure to Schistosoma mansoni larvae is dependent upon interleukin-10

The effect that multiple percutaneous exposures to Schistosoma larvae has on the development of early CD4 lymphocyte reac-tivity 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) of Schistosoma mansoni cercariae, compared to a single dose (1), results in CD4 T cell hyporesponsiveness within the skin-draining lymph nodes (sdLN), manifested as re-duced CD4 cell proliferation and cytokine production. FoxP3 CD4 regulatory T cells were present in similar numbers in the sdLN of 4 and 1mice and thus are unlikely to have a role in effecting hyporesponsiveness. Moreover, anergy of the CD4 cell population from 4mice was slight, as proliferation was only partly circumvented through the in vitro addition of exogenous interleukin-2 (IL-2), and the in vivo blockade 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 4mice deficient for IL-10 were readily able to proliferate, unlike those from 4wild-type cohorts. CD4 cells from the sdLN of 4mice exhib-ited 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 in-volving CD4 cell apoptosis. Schistosomiasis is a disease caused by parasitic helminths ofSchistosoma sp. and affects230 million people worldwide (1, 2), with a further 779 million people at risk of infection (3, 4). I