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Adult worms of Schistosoma mansoni live in the bloodstream, employing immune evasion strategies and exposing few antigens to the immune system. The tegumental surface of adult worms presents Sm60, a mannose-binding protein, which induces neutrophil migration and mast cell degranulation. Here we demonstrated that Sm60 is able to block the in vitro antigen-specific or polyclonal spleen cell proliferation induced by keyhole limpet haemocyanin (KLH) or concanavalin A (Con A), respectively. To address the mechanism of inhibition, we evaluated some cytokines in culture and observed that Sm60 decreased significantly the synthesis of interleukin (IL)-2 induced in response to KLH, but not other cytokines. To block the suppression triggered by Sm60, exogenous IL-2 or α-methyl-mannoside were added to KLHstimulated cultures pulsed with Sm60. Only IL-2 abolished the Sm60 effect, suggesting that Sm60 blocked the lymphoproliferation through the inhibition of IL-2 production, in a carbohydrate recognition domain (CRD)-independent mechanism. Our results suggest that Sm60 could participate in the immune evasion mechanisms of S. mansoni.