Deficiency in the transcription factor interferon regulatory factor (IRF)-2 leads to severely compromised development of natural killer and T helper type 1 cells.
Interferon (IFN) regulatory factor (IRF)-2 was originally described as an antagonist of IRF-1-mediated transcriptional regulation of IFN-inducible genes. IRF-1(-/)- mice exhibit defective T helper type 1 (Th1) cell differentiation. We have used experimental leishmaniasis to show that, like IRF-1(-/)- mice, IRF-2(-/)- mice are susceptible to Leishmania major infection due to a defect in Th1 differentiation. Natural killer (NK) cell development is compromised in both IRF-1(-/)- and IRF-2(-/)- mice, but the underlying mechanism differs. NK (but not NK(+) T) cell numbers are decreased in IRF-2(-/)- mice, and the NK cells that are present are immature in phenotype. Therefore, like IRF-1, IRF-2 is required for normal generation of Th1 responses and for NK cell development in vivo. In this particular circumstance the absence of IRF-2 cannot be compensated for by the presence of IRF-1 alone. Mechanistically, IRF-2 may act as a functional agonist rather than antagonist of IRF-1 for some, but not all, IFN-stimulated regulatory element (ISRE)-responsive genes.
Institut für Klinische Mikrobiologie und Immunologie, Universität Erlangen, 91054 Erlangen, Germany.
M
M
Lohoff
G S
GS
Duncan
D
D
Ferrick
H W
HW
Mittrücker
S
S
Bischof
S
S
Prechtl
M
M
Röllinghoff
E
E
Schmitt
A
A
Pahl
T W
TW
Mak
D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D050836:Interferon Regulatory Factor-2; D018664:Interleukin-12 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000097:blood / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D012097:Repressor Proteins; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D014157:Transcription Factors / Q000502:physiology*
D004268:DNA-Binding Proteins; D050836:Interferon Regulatory Factor-2; D019409:Interleukin-15; C494230:Irf2 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D018664:Interleukin-12; D009569:Nitric Oxide