Susceptibility of interleukin-2-deficient mice to Toxoplasma gondii is associated with a defect in the production of gamma interferon

Abstract

Costimulation through the B7-CD28 interaction is an important second signal for T-cell activation, and previous studies have shown that CD28-/- mice infected with Toxoplasma gondii generate suboptimal CD4+ T-cell responses, associated with a defect in production of the T-cell growth factor interleukin-2 (IL-2). To address the role of IL-2 in the expansion of T cells during toxoplasmosis, IL-2-/- mice were infected with T. gondii and their ability to generate a protective T-cell response was assessed. Although IL-2-/- mice produced normal levels of IL-12p40, they had reduced levels of gamma interferon (IFN-γ) in serum, had an increased parasite burden, and succumbed to infection with T. gondii within 20 days. Fluorescence-activated cell sorter analysis revealed that, although uninfected IL-2-/- mice had an increased number of activated T cells compared with uninfected IL-2+/+ mice, following infection they were unable to further upregulate this population. Examination of the ability of splenocytes from uninfected and infected mice to produce IFN-γ revealed that IL-2-/- mice were hyporesponsive to stimulation with anti-CD3 or parasite antigen compared with wild-type mice, and the addition of IL-2 alone or in combination with IL-12 or stimulation with phorbol myristate acetate and ionomycin did not restore the production of IFN-γ. Together, these studies reveal that IL-2-/- mice are unable to generate a protective IFN-γ response following infection with T. gondii and suggest that IL-2-/- mice have an intrinsic defect in their ability to activate and expand IFN-γ-producing T cells required for resistance to T. gondii.