NF-kappa B1 is required for optimal CD4+ Th1 cell development and resistance to Leishmania major.
The NF-kappaB family of transcription factors regulates the expression of a wide range of immune response genes involved in immunity to pathogens. However, the need for individual family members in regulating innate and adaptive immune responses in vivo has yet to be clearly defined. We investigated the role of NF-kappaB1 in the induction of protective IL-12-dependent Th1 cell responses following infection with the intracellular protozoan parasite Leishmania major. Whereas wild-type C57BL/6 mice controlled parasite replication, NF-kappaB1 knockout (KO) mice were susceptible to infection, developing chronic unresolving lesions associated with persistent parasites. There was a profound defect in Ag-specific CD4(+) T cell proliferation and IFN-gamma production in infected KO mice, although innate responses-including IL-12 production and control of intracellular parasite replication by macrophages-were intact. In vitro polyclonal stimulation of purified naive KO T cells revealed an intrinsic defect in CD4(+) T cell proliferation associated with reduced IL-2 receptor expression, but operating independently of APC function and IL-2 production. Critically, the frequency of proliferating KO CD4(+) T cells secreting IFN-gamma matched that of wild-type cells, suggesting that NF-kappaB1 was not required for efficient transcription of the IFN-gamma gene. Taken together, these results identify a novel role for NF-kappaB1 in CD4(+) T cell proliferation and the development of Th1 cell responses required for protective immunity against intracellular pathogens.
Artis
David
D
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, PA 19104, USA.
Speirs
Kendra
K
Joyce
Karen
K
Goldschmidt
Michael
M
Caamaño
Jorge
J
Hunter
Christopher A
CA
Scott
Phillip
P
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D007106:Immune Sera / Q000494:pharmacology; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000172:deficiency; D018664:Interleukin-12 / Q000096:biosynthesis; D018320:Leishmania major / Q000254:growth & development / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000172:deficiency; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D018106:CD28 Antigens; D017252:CD3 Complex; D007106:Immune Sera; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D015375:Receptors, Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma