IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity.
Dendritic cells (DCs) are bone marrow (BM)-derived APCs central to both innate and adaptive immunity. DCs are a heterogeneous cell population composed of multiple subsets with diverse functions. The mechanism governing the generation of multiple DC subsets is, however, poorly understood. In this study we investigated the roles of closely related transcription factors, IFN regulatory factor (IRF)-4 and IRF-8, in DC development by analyzing IRF-4(-/-), IRF-8(-/-), and IRF-4(-/-)IRF-8(-/-) (double-knockout) mice. We found that IRF-4 is required for the generation of CD4(+) DCs, whereas IRF-8 is, as reported previously, essential for CD8alpha(+) DCs. Both IRFs support the development of CD4(-)CD8alpha(-) DCs. IRF-8 and, to a lesser degree, IRF-4 contribute to plasmacytoid DC (PDC) development. Thus, the two IRFs together regulate the development of all conventional DCs as well as PDCs. Consistent with these findings, IRF-4, but not IRF-8, was expressed in CD4(+) DCs, whereas only IRF-8 was expressed in CD8alpha(+) DCs. CD4(-)CD8alpha(-) DCs and PDCs expressed both IRFs. We also demonstrate in vitro that GM-CSF-mediated DC differentiation depends on IRF-4, whereas Fms-like tyrosine kinase 3 ligand-mediated differentiation depends mainly on IRF-8. Gene transfer experiments with double-knockout BM cells showed that both IRFs have an overlapping activity and stimulate a common process of DC development. Nonetheless, each IRF also possesses a distinct activity to stimulate subset-specific gene expression, leading to the generation of functionally divergent DCs. Together, IRF-4 and IRF-8 serve as a backbone of the molecular program regulating DC subset development and their functional diversity.
Tamura
Tomohiko
T
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. tamurant@mail.nih.gov
Tailor
Prafullakumar
P
Yamaoka
Kunihiro
K
Kong
Hee Jeong
HJ
Tsujimura
Hideki
H
O'Shea
John J
JJ
Singh
Harinder
H
Ozato
Keiko
K
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha / Q000096:biosynthesis / Q000172:deficiency; D018664:Interleukin-12 / Q000096:biosynthesis / Q000172:deficiency; D053762:Interleukin-12 Subunit p40; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D021122:Protein Subunits / Q000096:biosynthesis / Q000172:deficiency; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
D004268:DNA-Binding Proteins; D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D018664:Interleukin-12; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D012097:Repressor Proteins; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4