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 regulation of innate and adaptive immune functions associated with resistance to infection. To assess the role of NF-kappaB(2) in the regulation of cell-mediated immunity, mice deficient in the NF-kappaB(2) gene (NF-kappaB(2)(-/-)) 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-gamma necessary to control replication of this parasite. Although wild-type controls were resistant to T. gondii, 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 contrast, during the chronic phase of the infection, susceptibility of NF-kappaB(2)(-/-) mice to toxoplasmic encephalitis was associated with a reduced capacity of their splenocytes to produce IFN-gamma 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-kappaB(2)(-/-) mice. Together, these results suggest a role for NF-kappaB(2) 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.
Caamaño
J
J
Medical Research Council Centre for Immune Regulation, School of Medicine, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Tato
C
C
Cai
G
G
Villegas
E N
EN
Speirs
K
K
Craig
L
L
Alexander
J
J
Hunter
C A
CA
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002908:Chronic Disease; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004660:Encephalitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D007111:Immunity, Cellular / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D052003:NF-kappa B p52 Subunit; D013601:T-Lymphocytes / Q000276:immunology*; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016781:Toxoplasmosis, Cerebral / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019014:fas Receptor / Q000096:biosynthesis
D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D019014:fas Receptor; D018664:Interleukin-12; D007371:Interferon-gamma