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ICSBP Is Essential for the Development of Mouse Type I Interferon-producing Cells and for the Generation and Activation of CD8⁺ Dendritic Cells

Giovanna Schiavoni¹, Fabrizio Mattei¹, Paola Sestili¹, Paola Borghi¹, Massimo Venditti¹, Herbert C. Morse, III², Filippo Belardelli¹ and Lucia Gabriele¹

¹ Laboratory of Virology, Istituto Superiore di Sanità, 00161 Rome, Italy
² Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Address correspondence to L. Gabriele, Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. Phone: 39-06-49903291; Fax: 39-06-49902097; E-mail: gabrilci{at}iss.it

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^lowB220⁺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 CD8 marker (CD8⁺ DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP^-/- CD8⁺ 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 CD8⁺ DCs, whose impairment in ICSBP^-/- mice can be responsible for the defective generation of a Th1 type of immune response.

Key Words: transcription factor • dendritic cell subsets • interferon • differentiation • maturation

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