Enhanced TCR-induced apoptosis in interferon regulatory factor 4-deficient CD4(+) Th cells.
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.
Lohoff
Michael
M
Advanced Medical Discovery Institute, 620 University Ave, Suite 706, Toronto, Ontario, Canada M5G 2C1.
Mittrücker
Hans-Willi
HW
Brüstle
Anne
A
Sommer
Frank
F
Casper
Bärbel
B
Huber
Magda
M
Ferrick
David A
DA
Duncan
Gordon S
GS
Mak
Tak W
TW
D000818:Animals; D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002455:Cell Division; D004396:Coloring Agents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005434:Flow Cytometry; D020287:In Situ Nick-End Labeling; D050835:Interferon Regulatory Factors; D018320:Leishmania major / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D019014:fas Receptor / Q000096:biosynthesis; D000099218:Interferon Regulatory Factor-4
D017304:Annexin A5; D015704:CD4 Antigens; D004396:Coloring Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D019014:fas Receptor; D000099218:Interferon Regulatory Factor-4