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T helper type 2 (Th2) responses are central to the control of helminth infections, but sensitive to opposing cytokine signals favoring Th1 priming. We previously reported on GATA-3+ T-bet+ Th2/1 hybrid cell differentiation in helminth mono-infections, resulting in a substantial proportion of cells co-producing IFN-γ next to Th2 cytokines. Here we demonstrate Th2/1 cells as the major source of parasite-specific IFN-γ production in acute and chronic infections with the enteric nematode Heligmosomoides polygyrus. Th2/1 cells differentiated from naive precursors and accumulated in spleen and intestine of infected mice, resulting in increased systemic and mucosal IFN-γ production. IFN-γ supplementation early during infection supported Th2/1 differentiation, associated with elevated parasite fecundity and the maintenance of high worm burdens in the chronic stage of infection, whereas mice lacking IFN-γ signals generated poor Th2/1 responses and restricted parasite fecundity more efficiently. These findings suggest that Th2/1 hybrid responses take part in immune regulation during helminth infection and restrain effective anti-helminth immunity. This article is protected by copyright. All rights reserved.