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J. Exp. Med.,
Volume 186, Number 9, November 3, 1997 1535-1546
By
From the * Laboratory of Immunopathology and 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 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 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.
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