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B1 Is Required for Optimal CD4+ Th1 Cell Development and Resistance to Leishmania major 1
* Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and
Medical Research Council Center for Immune Regulation, School of Medicine, University of Birmingham, Birmingham, United Kingdom
The NF-
B 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-B1 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-B1 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-
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- matched that of wild-type cells, suggesting that NF-B1 was not required for efficient transcription of the IFN- gene. Taken together, these results identify a novel role for NF-B1 in CD4+ T cell proliferation and the development of Th1 cell responses required for protective immunity against intracellular pathogens.
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