CD4+ T cells play critical roles in protection against the blood stage of malarial infection; however, their uncontrolled activation can be harmful to the host. In this study, in which rodent models ofPlasmodiumparasites were used, the expression of inhibitory receptors on activated CD4+ T cells and their cytokine production was compared with their expression in a bacterial and another protozoan infection. CD4+ T cells from mice infected withP. yoelii17XL,P yoelii17XNL,P. chabaudi,P. vinckeiandP. bergheiexpressed the inhibitory receptors, PD-1 and LAG-3, as early as 6 days after infection, whereas those from eitherListeria monocytogenes- orLeishmania major-infected mice did not. In response to T-cell receptor stimulation, CD4+ T cells from mice infected with all the pathogens under study produced high concentrations of IFN-γ. IL-2 production was reduced in mice infected withPlasmodiumspecies, but not in those infected withListeriaorLeishmania.In vitroblockade of the interaction between PD-1 and its ligands resulted in increased IFN-γ production in response toPlasmodiumantigens, implying that PD-1 expressed on activated CD4+ T cells actively inhibits T cell immune responses. Studies usingMyd88−/−,Trif−/− andIrf3−/− mice showed that induction of these CD4+ T cells and their ability to produce cytokines is largely independent of TLR signaling. These studies suggest that expression of the inhibitory receptors PD-1 and LAG-3 on CD4+ T cells and their reduced IL-2 production are common characteristic features ofPlasmodiuminfection.