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B Activity in T and NK Cells Results in Defective Effector Cell Expansion and Production of IFN-
Required for Resistance to Toxoplasma gondii1
* Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104;
Medical Research Council Center for Immune Regulation, University of Birmingham Medical School, Birmingham, United Kingdom; and
Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232
To define the role of NF-
B in the development of T cell responses required for resistance to Toxoplasma gondii, mice in which T cells are transgenic for a degradation-resistant (
N) form of IB
, an inhibitor of NF-B, were challenged with T. gondii and their response to infection compared with control mice. IB(N)-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-
, 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-. Together, these studies reveal that inhibition of NF-B activity in T and NK cells results in defective effector cell expansion and production of IFN- required for resistance to T. gondii.
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