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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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2002-05-1327v1
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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 CD8alpha + 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 CD8alpha 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 CD8alpha 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.

© 2003 by The American Society of Hematology.
 

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