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Blood, 15 March 2004, Vol. 103, No. 6, pp. 2221-2228.
Prepublished online as a Blood First Edition Paper on November 13, 2003; DOI 10.1182/blood-2003-09-3007.


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IMMUNOBIOLOGY

ICSBP is critically involved in the normal development and trafficking of Langerhans cells and dermal dendritic cells

Giovanna Schiavoni, Fabrizio Mattei, Paola Borghi, Paola Sestili, Massimo Venditti, Herbert C. Morse, III, Filippo Belardelli, and Lucia Gabriele

From the Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy; and Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Interferon consensus sequence-binding protein (ICSBP) is a transcription factor belonging to the interferon regulatory factor (IRF) family, recently shown to play a critical role in dendritic cell (DC) differentiation. Here, we analyzed the role of ICSBP in the development and trafficking of epidermal Langerhans cells (LCs) and dermal DCs and the implications for initiation of a competent immune response. ICSBP-/- mice exhibited a reduced frequency of LCs and a delayed mobility of DCs from skin that reflected a slower turnover rate in lymph nodes during steady-state conditions. Even under inflammatory changes, ICSBP-/- DCs displayed reduced mobility from skin to lymph nodes and, as a consequence, failed to induce a contact hypersensitivity (CHS) response, suggesting that these DCs were unable to initiate a competent antigen (Ag)–specific T-cell–mediated immunity. Moreover, bone marrow (BM)–derived DCs from ICSBP-/- mice exhibited an immature phenotype and a severe reduction of interleukin 12 (IL-12) expression. These BM DCs also showed a marked defect in their migratory response to macrophage inflammatory protein 3{alpha} (MIP-3{alpha}), MIP-3{beta}, and the CC chemokine CCL21/6Ckine, which was paralleled by an impaired expression of the CC chemokine receptors, CCR6 and CCR7. Together, these results indicate that ICSBP is critically required for the development and trafficking of skin DCs, thus playing a critical role in the DC-mediated initiation of T-cell immunity.


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