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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.

Giese NA, Gabriele L, Doherty TM, Klinman DM, Tadesse-Heath L, Contursi C, Epstein SL, Morse HC - J. Exp. Med. (1997)

Bottom Line: 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.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-gamma and macrophages of producing nitric oxide.This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0760, USA. ngiese@atlas.niaid.nih.gov

ABSTRACT
Mice with a 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-gamma 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-gamma 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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Course of L. major infection in ICSBP mutant mice. (A)  Swelling of infected footpads of ICSBP−/− (KO; n = 15) and ICSBP+/+  (WT; n = 10) mice was assessed as described in Material and Methods.  (B) Expression of genes involved in control of the resistance to L. major by  ICSBP−/− mice. RT-PCR analysis was performed on DLN cells. 7-wk  data represent RNA expression in DLNs obtained on day 49 after infection. Identical results were obtained for DLNs on day 53. (C) Impairment  of IFN-γ but not IL-4 production by DLN cells obtained from infected  ICSBP−/− mice after restimulation with SLA and Con A in vitro. Data  indicate the mean ± SEM in supernatants of 8 × 106 cells/ml derived  from 7-wk–infected ICSBP−/− (KO) and ICSBP+/+ (WT) mice. A summary of two separate experiments conducted on day 49 and day 53 after  infection is shown.
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Figure 3: Course of L. major infection in ICSBP mutant mice. (A) Swelling of infected footpads of ICSBP−/− (KO; n = 15) and ICSBP+/+ (WT; n = 10) mice was assessed as described in Material and Methods. (B) Expression of genes involved in control of the resistance to L. major by ICSBP−/− mice. RT-PCR analysis was performed on DLN cells. 7-wk data represent RNA expression in DLNs obtained on day 49 after infection. Identical results were obtained for DLNs on day 53. (C) Impairment of IFN-γ but not IL-4 production by DLN cells obtained from infected ICSBP−/− mice after restimulation with SLA and Con A in vitro. Data indicate the mean ± SEM in supernatants of 8 × 106 cells/ml derived from 7-wk–infected ICSBP−/− (KO) and ICSBP+/+ (WT) mice. A summary of two separate experiments conducted on day 49 and day 53 after infection is shown.

Mentions: The combinations of IFN-γ with LPS or CD40L are very effective at stimulating IL-12 production by macrophages, granulocytes, and dendritic cells (42–46). Recent studies, however, demonstrated the greater effectiveness of unmethylated CpG motifs present in bacterial DNA at stimulating B cells to produce IL-12 (26). In a second set of experiments, we used an ELISpot assay to determine the frequencies of lymph node and spleen cells producing IL-12 after stimulation with synthetic CpG-containing ODNs or bacterial DNA from E. coli (Fig. 2 B). Although ODNs and E. coli DNA induced IL-12 production in mice of either genotype with ODNs being more potent, the proportion of ICSBP−/− spleen cells that could be triggered to secrete IL-12 was much lower than that from wild-type spleen cells; however, the fold increase in the number of IL-12–secreting spleen cells stimulated with ODNs was 11 for the knockout mice versus 4 for wild-type mice (Fig. 2 B). The difference in the absolute numbers of IL-12–secreting cells, as well as the degree of activation, was less dramatic for lymph node cells. E. coli DNA triggered a threefold increase and ODNs a six- to sevenfold increase in the quantity of the IL-12 producers, regardless of genotype. Of interest, the frequencies of IL-12–secreting cells among unstimulated spleen and lymph node cells of wild-type mice were substantially higher than those in cultures from ICSBP-deficient mice, an observation in keeping with the relative levels of IL-12p40 transcripts (Figs. 1 B, 2 B, and 3 B).


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.

Giese NA, Gabriele L, Doherty TM, Klinman DM, Tadesse-Heath L, Contursi C, Epstein SL, Morse HC - J. Exp. Med. (1997)

Course of L. major infection in ICSBP mutant mice. (A)  Swelling of infected footpads of ICSBP−/− (KO; n = 15) and ICSBP+/+  (WT; n = 10) mice was assessed as described in Material and Methods.  (B) Expression of genes involved in control of the resistance to L. major by  ICSBP−/− mice. RT-PCR analysis was performed on DLN cells. 7-wk  data represent RNA expression in DLNs obtained on day 49 after infection. Identical results were obtained for DLNs on day 53. (C) Impairment  of IFN-γ but not IL-4 production by DLN cells obtained from infected  ICSBP−/− mice after restimulation with SLA and Con A in vitro. Data  indicate the mean ± SEM in supernatants of 8 × 106 cells/ml derived  from 7-wk–infected ICSBP−/− (KO) and ICSBP+/+ (WT) mice. A summary of two separate experiments conducted on day 49 and day 53 after  infection is shown.
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Figure 3: Course of L. major infection in ICSBP mutant mice. (A) Swelling of infected footpads of ICSBP−/− (KO; n = 15) and ICSBP+/+ (WT; n = 10) mice was assessed as described in Material and Methods. (B) Expression of genes involved in control of the resistance to L. major by ICSBP−/− mice. RT-PCR analysis was performed on DLN cells. 7-wk data represent RNA expression in DLNs obtained on day 49 after infection. Identical results were obtained for DLNs on day 53. (C) Impairment of IFN-γ but not IL-4 production by DLN cells obtained from infected ICSBP−/− mice after restimulation with SLA and Con A in vitro. Data indicate the mean ± SEM in supernatants of 8 × 106 cells/ml derived from 7-wk–infected ICSBP−/− (KO) and ICSBP+/+ (WT) mice. A summary of two separate experiments conducted on day 49 and day 53 after infection is shown.
Mentions: The combinations of IFN-γ with LPS or CD40L are very effective at stimulating IL-12 production by macrophages, granulocytes, and dendritic cells (42–46). Recent studies, however, demonstrated the greater effectiveness of unmethylated CpG motifs present in bacterial DNA at stimulating B cells to produce IL-12 (26). In a second set of experiments, we used an ELISpot assay to determine the frequencies of lymph node and spleen cells producing IL-12 after stimulation with synthetic CpG-containing ODNs or bacterial DNA from E. coli (Fig. 2 B). Although ODNs and E. coli DNA induced IL-12 production in mice of either genotype with ODNs being more potent, the proportion of ICSBP−/− spleen cells that could be triggered to secrete IL-12 was much lower than that from wild-type spleen cells; however, the fold increase in the number of IL-12–secreting spleen cells stimulated with ODNs was 11 for the knockout mice versus 4 for wild-type mice (Fig. 2 B). The difference in the absolute numbers of IL-12–secreting cells, as well as the degree of activation, was less dramatic for lymph node cells. E. coli DNA triggered a threefold increase and ODNs a six- to sevenfold increase in the quantity of the IL-12 producers, regardless of genotype. Of interest, the frequencies of IL-12–secreting cells among unstimulated spleen and lymph node cells of wild-type mice were substantially higher than those in cultures from ICSBP-deficient mice, an observation in keeping with the relative levels of IL-12p40 transcripts (Figs. 1 B, 2 B, and 3 B).

Bottom Line: 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.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-gamma and macrophages of producing nitric oxide.This indicates that ICSBP is a deciding factor in Th responses governing humoral and cellular immunity through its role in regulating IL-12 expression.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0760, USA. ngiese@atlas.niaid.nih.gov

ABSTRACT
Mice with a 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-gamma 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-gamma 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.

Show MeSH
Related in: MedlinePlus