Deficiency in the Transcription Factor Interferon Regulatory Factor (IRF)-2 Leads to Severely Compromised Development of Natural Killer and T Helper Type 1 Cells

doi:10.1084/jem.192.3.325

Published online 31 July 2000.

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© The Rockefeller University Press, 0022-1007/2000/8/325/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 3, August 7, 2000 325-336

Original Article

Deficiency in the Transcription Factor Interferon Regulatory Factor (IRF)-2 Leads to Severely Compromised Development of Natural Killer and T Helper Type 1 Cells

Michael Lohoff^a, Gordon S. Duncan^c,d, David Ferrick^e, Hans-Willi Mittrücker^f, Susi Bischof^a, Stefan Prechtl^a, Martin Röllinghoff^a, Edgar Schmitt^g, Andreas Pahl^b, and Tak W. Mak^c,d
^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

Correspondence to: Tak W. Mak, Ontario Cancer Institute/Amgen Institute, 620 University Ave., Ste. 706, Toronto, Ontario M5G 2C1, Canada. Tel:416-204-2236 Fax:416-204-5300 E-mail:tmak{at}amgen.com.

Interferon (IFN) regulatory factor (IRF)-2 was originally describedas an antagonist of IRF-1–mediated transcriptional regulationof IFN-inducible genes. IRF-1^-/- mice exhibit defective T helpertype 1 (Th1) cell differentiation. We have used experimentalleishmaniasis to show that, like IRF-1^-/- mice, IRF-2^-/- miceare susceptible to Leishmania major infection due to a defectin Th1 differentiation. Natural killer (NK) cell developmentis compromised in both IRF-1^-/- and IRF-2^-/- mice, but the underlyingmechanism differs. NK (but not NK⁺ T) cell numbers are decreasedin IRF-2^-/- mice, and the NK cells that are present are immaturein phenotype. Therefore, like IRF-1, IRF-2 is required for normalgeneration of Th1 responses and for NK cell development in vivo.In this particular circumstance the absence of IRF-2 cannotbe compensated for by the presence of IRF-1 alone. Mechanistically,IRF-2 may act as a functional agonist rather than antagonistof 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

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