Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4.
Certain IFN regulatory factor (IRF) transcription factors indirectly influence T helper (Th) cell differentiation by regulating the production of IL-12. Here, we show that IRF4 directly regulates Th cell differentiation in vitro and in vivo during murine leishmaniasis. In the absence of IRF4, IL-12-induced Th1 cell differentiation was compromised, while IL-4 failed to induce Th2 cell differentiation. Instead, IL-4 tended to induce Th1 cells, defined by production of IFN-gamma and TNF. Although early IL-4 signaling was normal in IRF4(-/-) Th cells, the protein GATA-3, a transcription factor critical for Th2 development, was not up-regulated following IL-4 treatment. Retroviral overexpression of GATA-3 rescued Th2 differentiation. Therefore, IRF4 deficiency manifests itself as severely dysregulated Th cell differentiation.
Institut für Medizinische Mikrobiologie, Pilgrimstein 2, 35037 Marburg, Germany.
Michael
M
Lohoff
Hans-Willi
HW
Mittrücker
Stefan
S
Prechtl
Susi
S
Bischof
Frank
F
Sommer
Sonja
S
Kock
David A
DA
Ferrick
Gordon S
GS
Duncan
Andre
A
Gessner
Tak W
TW
Mak
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D050990:GATA3 Transcription Factor; D005786:Gene Expression Regulation / Q000187:drug effects; D050835:Interferon Regulatory Factors; D015847:Interleukin-4 / Q000494:pharmacology; D007896:Leishmaniasis / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D050800:STAT6 Transcription Factor; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D000099218:Interferon Regulatory Factor-4
D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; D050835:Interferon Regulatory Factors; D015847:Interleukin-4; D050800:STAT6 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000099218:Interferon Regulatory Factor-4; C494748:Gata3 protein, mouse; C494100:Stat6 protein, mouse