Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Published online before print September 11, 2006
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0406246

Received for publication April 5, 2006.
Revised July 14, 2006.
Accepted for publication August 8, 2006.

Article

IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features

L. Gabriele *, A. Fragale {dagger}, P. Borghi *, P. Sestili *, E. Stellacci {dagger}, M. Venditti *, G. Schiavoni *, M. Sanchez *, F. Belardelli *, and A. Battistini {dagger}@

Departments of *Cell Biology and Neurosciences and {dagger}Infectious, Parasitic and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy

@ To whom correspondence should be addressed. E-mail: battist{at}iss.it.


  Abstract

Members of the IFN regulatory factors (IRFs) family are transcriptional regulators that play essential roles in the homeostasis and function of the immune system. Recent studies indicate a direct involvement of some members of the family in the development of different subsets of dendritic cells (DC). Here, we report that IRF-1 is a potent modulator of the development and functional maturation of DC. IRF-1-deficient mice (IRF-1-/-) exhibited a predominance of plasmacytoid DC and a selective reduction of conventional DC, especially the CD8{alpha}+ subset. IRF-1-/- splenic DC were markedly impaired in their ability to produce proinflammatory cytokines such as IL-12. By contrast, they expressed high levels of IL-10, TGF-{beta}, and the tolerogenic enzyme indoleamine 2,3 dioxygenase. As a consequence, IRF-1-/- DC were unable to undergo full maturation and retained plasmacytoid and tolerogenic characteristics following virus infection ex vivo and in vivo. Accordingly, DC from IRF-1-/- mice were less efficient in stimulating the proliferation of allogeneic T cells and instead, induced an IL-10-mediated, suppressive activity in allogeneic CD4+CD25+ regulatory T cells. Together, these results indicate that IRF-1 is a key regulator of DC differentiation and maturation, exerting a variety of effects on the functional activation and tolerogenic potential of these cells.

Key Words: cytokines • virus infections • tolerance • IFN regulatory factors




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A. Fragale, L. Gabriele, E. Stellacci, P. Borghi, E. Perrotti, R. Ilari, A. Lanciotti, A. L. Remoli, M. Venditti, F. Belardelli, et al.
IFN Regulatory Factor-1 Negatively Regulates CD4+CD25+ Regulatory T Cell Differentiation by Repressing Foxp3 Expression
J. Immunol., August 1, 2008; 181(3): 1673 - 1682.
[Abstract] [Full Text] [PDF]


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