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Original Article

^a Institut für Klinische Mikrobiologie und Immunologie, Universität Erlangen, 91054 Erlangen, Germany
^b Institut für Pharmakologie, Universität Erlangen, 91054 Erlangen, Germany
^c Amgen Research Institute, Toronto, Ontario M5G 2C1, Canada
^d Ontario Cancer Institute, Department of Immunology, and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada
^e Department of Pathology, Department of Microbiology, and the Department of Immunology, School of Veterinary Medicine, University of California at Davis, Davis, California 95616
^f Max Planck Institut für Infektionsbiologie, 10117 Berlin, Germany
^g Institut für Immunologie, Universität Mainz, 55101 Mainz, Germany
Ontario Cancer Institute/Amgen Institute, 620 University Ave., Ste. 706, Toronto, Ontario M5G 2C1, Canada.416-204-5300416-204-2236

tmak{at}amgen.com

Interferon (IFN) regulatory factor (IRF)-2 was originally described as an antagonist of IRF-1–mediated transcriptional regulation of IFN-inducible genes. IRF-1^–/– mice exhibit defective T helper type 1 (Th1) cell differentiation. We have used experimental leishmaniasis to show that, like IRF-1^–/– mice, IRF-2^–/– mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation. Natural killer (NK) cell development is compromised in both IRF-1^–/– and IRF-2^–/– mice, but the underlying mechanism differs. NK (but not NK⁺ T) cell numbers are decreased in IRF-2^–/– mice, and the NK cells that are present are immature in phenotype. Therefore, like IRF-1, IRF-2 is required for normal generation of Th1 responses and for NK cell development in vivo. In this particular circumstance the absence of IRF-2 cannot be compensated for by the presence of IRF-1 alone. Mechanistically, IRF-2 may act as a functional agonist rather than antagonist of IRF-1 for some, but not all, IFN-stimulated regulatory element (ISRE)-responsive genes.

Key Words: interferon regulatory factor • Th1 • natural killer cells • Leishmania • interleukin 15

Abbreviations used in this paper: APC, allophycocyanin; BM, bone marrow; BrdU, bromodeoxyuridine; ICSBP, IFN consensus sequencing binding protein; IRF, IFN regulatory factor; iNOS, inducible NO synthase; ISRE, IFN-stimulated regulatory element; LNC, LN cell; M, macrophage(s); NO, nitric oxide; PEC, peritoneal exudate cell; RAG, recombination activating gene; RT, reverse transcription; SN, supernatant.

© 2000 The Rockefeller University Press

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