Identification of a role for NF-kappa B2 in the regulation of apoptosis and in maintenance of T cell-mediated immunity to Toxoplasma gondii

The NF-kappaB family of transcription factors are involved in the regulatio n of innate and adaptive immune functions associated with resistance to inf ection. To assess the role of NF-kappaB(2) in the regulation of cell-mediat ed immunity, mice deficient in the NF-kappaB(2) gene (NF-kappaB(2)(-/-)) we re challenged with the intracellular parasite Toxoplasma gondii, Resistance to this opportunistic pathogen Is dependent on the production of IL-12, wh ich is required for the development of innate NK cell and adaptive T cell r esponses dominated by the production of IFN-gamma necessary to control repl ication of this parasite. Although mild-type controls were resistant to T.g ondii, NF-kappaB(2)(-/-) mice developed severe toxoplasmic encephalitis and succumbed to disease between 3 and 10 wk following infection. However, NF- kappaB(2) was not required for the ability of macrophages to produce IL-12 or to inhibit parasite replication and during the acute stage of infection, NF-kappaB(2)(-/-) mice had no defect in their ability to produce IL-12 or IFN-gamma and infection-induced NK cell responses appeared normal. In contr ast, during the chronic phase of the infection, susceptibility of NF-kappaB (2)(-/-) mice to toxoplasmic encephalitis was associated with a reduced cap acity of their splenocytes to produce IFN-gamma associated with a loss of C D4(+) and CD8(+) T cells, This loss of T cells correlated with increased le vels of apoptosis and with elevated expression of the pro-apoptotic molecul e Fas by T cells from infected NF-kappaB(2)(-/-) mice. Together, these resu lts suggest a role for NF-kappaB(2)(-/-) in the regulation of lymphocyte ap optosis and a unique role for this transcription factor in maintenance of T cell responses required for long-term resistance to T. gondii.