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.
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19 July 2004
Brief Definitive Report|
July 12 2004
Enhanced TCR-induced Apoptosis in Interferon Regulatory Factor 4–deficient CD4+ Th Cells
Michael Lohoff,
Michael Lohoff
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
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Hans-Willi Mittrücker,
Hans-Willi Mittrücker
2Max-Planck Institut für Infektionsbiologie, 10117 Berlin, Germany
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Anne Brüstle,
Anne Brüstle
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
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Frank Sommer,
Frank Sommer
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
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Bärbel Casper,
Bärbel Casper
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
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Magda Huber,
Magda Huber
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
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David A. Ferrick,
David A. Ferrick
3School of Veterinary Medicine, University of California, Davis, CA 95616
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Gordon S. Duncan,
Gordon S. Duncan
4Advanced Medical Discovery Institute
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Tak W. Mak
Tak W. Mak
4Advanced Medical Discovery Institute
5Department of Immunology,
6Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1
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Michael Lohoff
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
Hans-Willi Mittrücker
2Max-Planck Institut für Infektionsbiologie, 10117 Berlin, Germany
Anne Brüstle
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
Frank Sommer
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
Bärbel Casper
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
Magda Huber
1Institut für Medizinische Mikrobiologie, 35037 Marburg, Germany
David A. Ferrick
3School of Veterinary Medicine, University of California, Davis, CA 95616
Gordon S. Duncan
4Advanced Medical Discovery Institute
Tak W. Mak
4Advanced Medical Discovery Institute
5Department of Immunology,
6Department 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: [email protected]
M. Lohoff and H.-W. Mittrücker contributed equally to this work.
Received:
January 29 2004
Accepted:
June 07 2004
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2004
J Exp Med (2004) 200 (2): 247–253.
Article history
Received:
January 29 2004
Accepted:
June 07 2004
Citation
Michael Lohoff, Hans-Willi Mittrücker, Anne Brüstle, Frank Sommer, Bärbel Casper, Magda Huber, David A. Ferrick, Gordon S. Duncan, Tak W. Mak; Enhanced TCR-induced Apoptosis in Interferon Regulatory Factor 4–deficient CD4+ Th Cells . J Exp Med 19 July 2004; 200 (2): 247–253. doi: https://doi.org/10.1084/jem.20040182
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