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Chronic Schistosoma infection is often characterized by a state of T cell hyporesponsiveness of the host. Suppression of dendritic cell (DC) function could be one of the mechanisms underlying this phenomenon, since Schistosoma antigens are potent modulators of dendritic cell function in vitro. Yet, it remains to be established whether DC function is modulated during chronic human Schistosoma infection in vivo. To address this question, the effect of Schistosoma haematobium infection on the function of human blood DC was evaluated. We found that plasmacytoid (pDC) and myeloid DC (mDC) from infected subjects were present at lower frequencies in peripheral blood and that mDC displayed lower expression levels of HLA-DR compared to those from uninfected individuals. Furthermore, mDC from infected subjects, but not pDC, were found to have a reduced capacity to respond to TLR ligands, as determined by MAPK signaling, cytokine production and expression of maturation markers. Moreover, the T cell activating capacity of TLR-matured mDC from infected subjects was lower, likely as a result of reduced HLA-DR expression. Collectively these data show that S. haematobium infection is associated with functional impairment of human DC function in vivo and provide new insights into the underlying mechanisms of T cell hyporesponsiveness during chronic schistosomiasis. Author Summary: A key feature of schistosomiasis, as well as of other systemic helminth infections, is their chronic nature. This reflects the successful evasion and suppression of host immune responses by the parasites. One of the mechanisms that could underlie this phenomenon is modulation of the dendritic cells (DC), which play a central role in initiation and control of T cell responses. Although several in vitro studies have documented the modulatory capacity of Schistosoma antigens on DC function, it is still unclear what effect schistosomiasis has on human DC function in vivo. To address this question, we isolated the two main DC subsets present in peripheral blood from infected and uninfected individuals living in a Schistosoma-endemic area in central Africa, and found that specifically the myeloid DC from Schistosoma-infected subjects displayed an impaired capacity to respond to Toll-like receptor ligands and to drive T cell responses. These findings provide new insights into how schistosomiasis suppresses host immune responses, which can be exploited for new strategies to enhance immunity against the parasites. [ABSTRACT FROM AUTHOR]