© The Rockefeller University Press, 0022-1007/1997/11/1535/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 9, November 3, 1997 1535-1546
Interferon (IFN) Consensus Sequence-binding Protein, a Transcription Factor of the IFN Regulatory Factor Family, Regulates Immune Responses In Vivo through Control of Interleukin 12 Expression
Nathalia A. Giese*,
Lucia Gabriele*,
T. Mark Doherty
,
Dennis M. Klinman¶,
Lekidelu Tadesse-Heath*,
Christina Contursi
,
Suzanne L. Epstein||, and
Herbert C. Morse, III*
From the * Laboratory of Immunopathology and
Laboratory of Parisitology, National Institute of Allergy and Infectious Diseases;
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-0760; and ¶ Division of Virology and || Division of Cell and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20852-1448
Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a chronic myelogenous leukemia-like syndrome and mount impaired responses to certain viral and bacterial infections. To gain a mechanistic understanding of the contributions of ICSBP to humoral and cellular immunity, we characterized the responses of control and ICSBP–/– mice to infection with influenza A (flu) and Leishmania major (L. major). Mice of both genotypes survived infections with flu, but differed markedly in the isotype distribution of antiflu antibodies. In sera of normal mice, immunoglobulin (Ig)G2a antibodies were dominant over IgG1 antibodies, a pattern indicative of a T helper cell type 1 (Th1)-driven response. In sera of ICSBP–/– mice, however, IgG1 antibodies dominated over IgG2a antibodies, a pattern indicative of a Th2-driven response. The dominance of IgG1 and IgE over IgG2a was detected in the sera of uninfected mice as well. A seeming Th2 bias of ICSBP-deficient mice was also uncovered in their inability to control infection with L. major, where resistance is known to be dependent on IL-12 and IFN-
as components of a Th1 response. Infected ICSBP-deficient mice developed fulminant, disseminated leishmaniasis as a result of failure to mount a Th1-mediated curative response, although T cells remained capable of secreting IFN-
and macrophages of producing nitric oxide. Compromised Th1 differentiation in ICSBP–/– mice could not be attributed to hyporesponsiveness of CD4+ T cells to interleukin (IL)-12; however, the ability of uninfected and infected ICSBP-deficient mice to produce IL-12 was markedly impaired. This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.
Address correspondence to Dr. N.A. Giese, LIP, NIAID, 7 Center Dr., MSC 0760, NIH, Bethesda, MD 20892-0760. Phone: 301-496-1150; FAX: 301-402-0077; E-mail: ngiese{at}atlas.niaid.nih.gov
1 Abbreviations used in this paper: CD40L, CD40 ligand; DLN, LN draining the site of infection; flu, influenza A; ICSBP, interferon consensus sequence-binding protein; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; NO, nitric oxide; ODN, oligodeoxynucleotide; RT, reverse transcriptase; SLA, soluble leishmanial antigen.

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