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PMID: 12461077 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

ICSBP is essential for the development of mouse type I interferon-producing cells and for the generation and activation of CD8alpha(+) dendritic cells.

The Journal of experimental medicine ·Vol. 196 ·No. 11 ·2002-12-02 ·Pages 1415-25

Schiavoni G, Mattei F, Sestili P, Borghi P, Venditti M, Morse HC, Belardelli F, Gabriele L

Abstract

Interferon (IFN) consensus sequence-binding protein (ICSBP) is a transcription factor playing a critical role in the regulation of lineage commitment, especially in myeloid cell differentiation. In this study, we have characterized the phenotype and activation pattern of subsets of dendritic cells (DCs) in ICSBP(-/-) mice. Remarkably, the recently identified mouse IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP(-/-) mice, as revealed by lack of CD11c(low)B220(+)Ly6C(+)CD11b(-) cells. In parallel, CD11c(+) cells isolated from ICSBP(-/-) spleens were unable to produce type I IFNs in response to viral stimulation. ICSBP(-/-) mice also displayed a marked reduction of the DC subset expressing the CD8alpha marker (CD8alpha(+) DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP(-/-) CD8alpha(+) DCs exhibited a markedly impaired phenotype when compared with WT DCs. They expressed very low levels of costimulatory molecules (intercellular adhesion molecule [ICAM]-1, CD40, CD80, CD86) and of the T cell area-homing chemokine receptor CCR7, whereas they showed higher levels of CCR2 and CCR6, as revealed by reverse transcription PCR. In addition, these cells were unable to undergo full phenotypic activation upon in vitro culture in presence of maturation stimuli such as lipopolysaccharide or poly (I:C), which paralleled with lack of Toll-like receptor (TLR)3 mRNA expression. Finally, cytokine expression pattern was also altered in ICSBP(-/-) DCs, as they did not express interleukin (IL)-12p40 or IL-15, but they displayed detectable IL-4 mRNA levels. On the whole, these results indicate that ICSBP is a crucial factor in the regulation of two possibly linked processes: (a) the development and activity of mIPCs, whose lack in ICSBP(-/-) mice may explain their high susceptibility to virus infections; (b) the generation and activation of CD8alpha(+) DCs, whose impairment in ICSBP(-/-) mice can be responsible for the defective generation of a Th1 type of immune response.

MeSH Terms
Animals Antigens, CD/analysis B7-1 Antigen/analysis B7-2 Antigen CD11a Antigen CD40 Antigens/analysis CD8 Antigens/analysis Cytokines/biosynthesis Dendritic Cells/immunology,physiology Intercellular Adhesion Molecule-1/analysis Interferon Regulatory Factors Interferon Type I/biosynthesis Membrane Glycoproteins/analysis Mice Mice, Inbred C57BL Receptors, Chemokine/analysis Repressor Proteins/physiology
Chemicals
Antigens, CD B7-1 Antigen B7-2 Antigen CD11a Antigen CD40 Antigens CD8 Antigens Cd86 protein, mouse Cytokines Interferon Regulatory Factors Interferon Type I Membrane Glycoproteins Receptors, Chemokine Repressor Proteins interferon regulatory factor-8 Intercellular Adhesion Molecule-1
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Schiavoni Giovanna
Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Mattei Fabrizio
Sestili Paola
Borghi Paola
Venditti Massimo
Morse Herbert C
Belardelli Filippo
Gabriele Lucia
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20021263
Published
2002-12-02
Pages
1415-25
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2194263
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20021263 PMC Full Text View journal details
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