INTERFERON (IFN) CONSENSUS SEQUENCE-BINDING PROTEIN, A TRANSCRIPTION FACTOR OF THE IFN REGULATORY FACTOR FAMILY, REGULATES IMMUNE-RESPONSESIN-VIVO THROUGH CONTROL OF INTERLEUKIN-12 EXPRESSION

Mice with a null mutation of the gene encoding interferon consensus se quence-binding protein (ICSBP) develop a chronic myelogenous leukemia- like syndrome and mount impaired responses to certain viral and bacter ial infections. To gain a mechanistic understanding of the contributio ns of ICSBP to humoral and cellular immunity, we characterized the res ponses of control and ICSBP-/- mice to infection with influenza A (flu ) and Leishmania major (L. major). Mice of both genotypes survived inf ections with flu, but differed markedly in the isotype distribution of antiflu antibodies. In sera of normal mice, immunoglobulin (Ig)G2a an tibodies 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 i ndicative of a Th2-driven response. The dominance of IgG1 and ISE 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 d ependent on IL-12 and IFN-gamma as components of a Th1 response. Infec ted ICSBP-deficient mice developed fulminant, disseminated leishmanias is as a result of failure to mount a Th1-mediated curative response, a lthough T cells remained capable of secreting IFN-gamma and macrophage s of producing nitric oxide. Compromised Th1 differentiation in ICSBP- /- mice could not be attributed to hyporesponsiveness of CD4(+) T cell s to interleukin (IL)-12; however, the ability of uninfected and infec ted ICSBP-deficient mice to produce IL-12 was markedly impaired. This indicates that ICSBP is a deciding factor in Th responses governing hu moral and cellular immunity through its role in regulating IL-12 expre ssion.