Production of IFN-γ by CD4 T cells is widely theorized to control Plasmodium parasite burden during blood-stage malaria. Surprisingly, the specific and crucial mechanisms through which this highly pleiotropic cytokine acts to confer protection against malarial disease remain largely untested in vivo. Here we used a CD4 T cell–restricted Cre-Lox IFN-γ excision mouse model to test whether and how CD4 T cell–derived IFN-γ controls blood-stage malaria. Although complete absence of IFN-γ compromised control of the acute and the chronic, recrudescent blood-stage infections with P. c. chabaudi, we identified a specific, albeit modest, role for CD4 T cell–derived IFN-γ in limiting parasite burden only during the chronic stages of P. c. chabaudi malaria. CD4 T cell IFN-γ promoted IgG Ab class switching to the IgG2c isotype during P. c. chabaudi malaria in C57BL/6 mice. Unexpectedly, our data do not support gross defects in phagocytic activity in IFN-γ-deficient hosts infected with blood-stage malaria. Together, our data confirm CD4 T cell–dependent roles for IFN-γ but suggest CD4 T cell–independent roles for IFN-γ in immune responses to blood-stage malaria.

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