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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-05-1327.
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Blood, 1 February 2003, Vol. 101, No. 3, pp. 961-969
IMMUNOBIOLOGY
ICSBP/IRF-8 retrovirus transduction rescues dendritic cell
development in vitro
Hideki Tsujimura,
Tomohiko Tamura,
Celine Gongora,
Julio Aliberti,
Caetano Reis e Sousa,
Alan Sher, and
Keiko Ozato
From the Laboratory of Molecular Growth Regulation,
National Institute of Child Health and Human Development, and
Laboratory of Parasite Diseases, National Institute of Allergy and
Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD;
and Immunobiology Laboratory, Cancer Research United Kingdom, London
Research Institute, London, United Kingdom.
Dendritic cells (DCs) develop from bone marrow (BM)
progenitor cells and mature in response to external signals to elicit functions important for innate and adaptive immunity. Interferon consensus sequence binding protein (ICSBP; also called interferon regulatory factor 8 [IRF-8]) is a hematopoietic
cell-specific transcription factor expressed in BM progenitor cells
that contributes to myeloid cell development. In light of our earlier
observation that ICSBP / mice lack CD8 +
DCs, we investigated the role of ICSBP in DC development in vitro in
the presence of Flt3 ligand. Immature ICSBP / DCs
developed from BM progenitor cells showed assorted defects, did not
mature in response to activation signals, and failed to express
CD8 and interleukin 12 (IL-12) p40, a feature consistent with
ICSBP / DCs in vivo. We show that retroviral
introduction of ICSBP restores the development of immature DCs that can
fully mature on activation signals. All the defects seen with
ICSBP / DCs were corrected after ICSBP transduction,
including the expression of CD8 and IL-12 p40 as well as major
histocompatability complex class II and other costimulatory molecules.
ICSBP is known to regulate gene expression by interacting with partner
proteins PU.1 and IRFs, thereby binding to target elements ISRE and
EICE. Analysis of a series of ICSBP mutants showed that the
intact DNA-binding activity as well as the ability to interact with
partner proteins are required for the restoration of DC
development/maturation, pointing to the transcriptional function of
ICSBP as a basis of restoration. Taken together, this study identifies
ICSBP as a factor critical for both early differentiation and final
maturation of DCs.

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