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B2 in the Regulation of Apoptosis and in Maintenance of T Cell-Mediated Immunity to Toxoplasma gondii1
*
Medical Research Council Centre for Immune Regulation, School of Medicine, University of Birmingham, Edgbaston, Birmingham, United Kingdom;
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104; and
Department of Immunology, The Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
The NF-
B family of transcription factors are involved in the
regulation of innate and adaptive immune functions associated with
resistance to infection. To assess the role of NF-B2 in
the regulation of cell-mediated immunity, mice deficient in the
NF-B2 gene (NF-B2-/-) were
challenged with the intracellular parasite Toxoplasma
gondii. Resistance to this opportunistic pathogen is dependent
on the production of IL-12, which is required for the development of
innate NK cell and adaptive T cell responses dominated by the
production of IFN-
necessary to control replication of this
parasite. Although wild-type controls were resistant to T.
gondii, NF-B2-/- mice developed
severe toxoplasmic encephalitis and succumbed to disease between 3 and
10 wk following infection. However, NF-B2 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-B2-/- mice had no defect in their
ability to produce IL-12 or IFN- and infection-induced NK cell
responses appeared normal. In contrast, during the chronic phase of the
infection, susceptibility of NF-B2-/- mice
to toxoplasmic encephalitis was associated with a reduced capacity of
their splenocytes to produce IFN- associated with a loss of
CD4+ and CD8+ T cells. This loss of T cells
correlated with increased levels of apoptosis and with elevated
expression of the pro-apoptotic molecule Fas by T cells from infected
NF-B2-/- mice. Together, these results
suggest a role for NF-B2 in the regulation of lymphocyte
apoptosis and a unique role for this transcription factor in
maintenance of T cell responses required for long-term resistance to
T. gondii.
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