Inhibition of NF-kappa B activity in T and NK cells results in defective effector cell expansion and production of IFN-gamma required for resistance to Toxoplasma gondii

• Published in: The Journal of immunology (1950) 2003-03, Vol.170 (6), p.3139-3146
• Main Authors: Tato, Cristina M, Villarino, Alejandro, Caamaño, Jorge H, Boothby, Mark, Hunter, Christopher A
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Protozoan - pharmacology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Cell Division - genetics; Cell Division - immunology; Cytotoxicity, Immunologic - genetics; Female; Genetic Predisposition to Disease; I-kappa B Proteins - genetics; Immunity, Innate - genetics; Interferon-gamma - biosynthesis; Interferon-gamma - physiology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Killer Cells, Natural - pathology; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Toxoplasma - immunology; Toxoplasmosis, Animal - genetics; Toxoplasmosis, Animal - immunology; Toxoplasmosis, Animal - pathology; Transgenes - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.6.3139

To define the role of NF-kappa 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 (Delta N) form of I kappa B alpha, an inhibitor of NF-kappa B, were challenged with T. gondii and their response to infection compared with control mice. I kappa B alpha(Delta 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-gamma, 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-gamma. Together, these studies reveal that inhibition of NF-kappa B activity in T and NK cells results in defective effector cell expansion and production of IFN-gamma required for resistance to T. gondii.