Inhibition of NF-κB Activity in T and NK Cells Results in Defective Effector Cell Expansion and Production of IFN-γ Required for Resistance to Toxoplasma gondii

Abstract

To define the role of NF-κB in the development of T cell responses required for resistance to Toxoplasma gondii, mice in which T cells are transgenic for a degradation-resistant (ΔN) form of IκBα, an inhibitor of NF-κB, were challenged with T. gondii and their response to infection compared with control mice. IκBα(ΔN)-transgenic (Tg) mice succumbed to T. gondii infection between days 12 and 35, and death was associated with an increased parasite burden compared with wild-type (Wt) controls. Analysis of the responses of infected mice revealed that IL-12 responses were comparable between strains, but Tg mice had a marked reduction in systemic levels of IFN-γ, the major mediator of resistance to T. gondii. In addition, the infection-induced increase in NK cell activity observed in Wt mice was absent from Tg mice and this correlated with NK cell expression of the transgene. Infection-induced activation of CD4+ T cells was similar in Wt and Tg mice, but expansion of activated CD4+T cells was markedly reduced in the Tg mice. This difference in T cell numbers correlated with a reduced capacity of these cells to proliferate after stimulation and was associated with a major defect in the ability of CD4+ T cells from infected mice to produce IFN-γ. Together, these studies reveal that inhibition of NF-κB activity in T and NK cells results in defective effector cell expansion and production of IFN-γ required for resistance to T. gondii.