The Journal of Experimental Medicine
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Published online 12 July 2004 doi:10.1084/jem.20040182
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 2, 247-253
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Brief Definitive Report

 Enhanced TCR-induced Apoptosis in Interferon Regulatory Factor 4–deficient CD4+ Th Cells

Michael Lohoff1, Hans-Willi Mittrücker2, Anne Brüstle1, Frank Sommer1, Bärbel Casper1, Magda Huber1, David A. Ferrick3, Gordon S. Duncan4, and Tak W. Mak4,5,6

1 Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
2 Max-Planck Institut für Infektionsbiologie, 10117 Berlin, Germany
3 School of Veterinary Medicine, University of California, Davis, CA 95616
4 Advanced Medical Discovery Institute, 5 Department of Immunology, and 6 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1

Address correspondence to Tak W. Mak, Advanced Medical Discovery Institute, 620 University Ave, Suite 706, Toronto, Ontario, Canada M5G 2C1. Phone: (416) 204-2236; Fax: (416) 204-5300; email: tmak{at}oci.utoronto.ca

Transcription factors of the interferon regulatory factor (IRF) family contribute to the regulation of cell proliferation and apoptosis. Here, we show that CD4+ T helper (Th) cells lacking IRF4 (IRF4–/–) are highly sensitive to apoptosis. After infection of IRF4–/– mice with the protozoan parasite Leishmania major, the lesion-draining lymph nodes developed the prototypic lymphadenopathy of wild-type mice after 4 wk, but demonstrated almost total loss of cellularity and enhanced apoptosis after 7 wk. In vitro, activation of IRF4–/– CD4+ Th cells led to greatly increased apoptosis compared with wild-type cells. Coculture of IRF4–/– and IRF4+/+ CD4+ cells did not increase survival of IRF4–/– CD4+ cells, indicating that the enhanced rate of IRF4–/– Th cell apoptosis was neither transferable nor due to lack of a cytokine. Enhanced CD4+ cell apoptosis was also observed after anti-CD95 mAb treatment, despite normal CD95 expression. Removal of endogenous cytokines, notably interleukin (IL)-4, led to increased and equally high levels of IRF4–/– and IRF4+/+ cell apoptosis, whereas the protective activity of exogenous IL-4 was reduced in IRF4–/– CD4+ cells despite normal expression of the IL-4 receptor. Therefore, IRF4 is central in protecting CD4+ cells against proapoptotic stimuli.

Key Words: Th cell • apoptosis • IRF4 • CD95 • Leishmania major • T helper cell • IL-4

M. Lohoff and H.-W. Mittrücker contributed equally to this work.


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