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. 1998 Aug;66(8):3818-24.
doi: 10.1128/IAI.66.8.3818-3824.1998.

Differential regulation of the interleukin-12 receptor during the innate immune response to Leishmania major

D Jones  1 , M M Elloso, L Showe, D Williams, G Trinchieri, P Scott
Affiliations

Differential regulation of the interleukin-12 receptor during the innate immune response to Leishmania major

D Jones et al. Infect Immun. 1998 Aug.

Abstract

Previous studies have shown the central role of interleukin 12 (IL-12) in the development of resistance to Leishmania major infection in C3H mice. We now show that during the innate immune response the lymph node cells of L. major-infected C3H mice upregulate the IL-12 receptor on CD4(+), CD8(+), and B220(+) cells. An increase in the ability of the lymph node cells to bind IL-12 correlates with 9.3- and 4.6-fold increases in the mRNA expression levels of the IL-12Rbeta1 and -beta2 subunits, respectively. In contrast, BALB/c mice, which are susceptible to L. major infection, have no increase in the ability of the lymph node cells to bind IL-12 and correspondingly smaller increases in the mRNA expression levels of the IL-12Rbeta1 and -beta2 subunits of 2- and 1.5-fold, respectively. Neutralizing IL-4 and the administration of exogenous IL-12 upregulate IL-12R expression in BALB/c mice, while the neutralization of IL-12 in C3H mice blocks increased IL-12 receptor expression. These experiments reveal an important role for the regulation of the IL-12 receptor during the innate immune response after infection of mice with a pathogen.

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Figures

FIG. 1
FIG. 1
IL-12 binding to LN cells from L. major-infected C3H and BALB/c mice. The results of a flow-cytometric analysis of IL-12 binding to lymphocytes isolated from the draining LNs of uninfected mice and mice infected 2 days previously are displayed. The data from one representative mouse from each group (n = 3 to 5) are shown. Peaks outlined by dark solid lines represent cells incubated with 0.5 μg of IL-12 and then stained with the anti-IL-12 MAb; these peaks are compared to those for control samples stained with the anti-IL-12 MAb alone (shaded peaks). These results are representative of four experiments.
FIG. 2
FIG. 2
IL-12 binding to LN cells and cell subsets from L. major-infected C3H mice. A two-color flow-cytometric analysis of IL-12 binding to lymphocyte subsets was performed with LN cells from C3H mice infected 2 days previously that were surface stained for CD4, CD8, or B220. Results show IL-12 binding by the total and gated populations. The peaks outlined by the dark solid lines and the shaded peaks are as defined in the legend for Fig. 1. These results are representative of four experiments.
FIG. 3
FIG. 3
IL-12 binding to LN cells from BALB/c mice given exogenous IL-12. Shown is a two-color flow-cytometric analysis of IL-12 binding to lymphocyte subsets using LN cells from BALB/c mice infected 2 days previously, BALB/c mice infected 2 days previously and treated in vivo with 0.2 μg of IL-12 at the time of infection, and BALB/c mice treated with 0.2 μg of IL-12 alone 2 days prior to analysis. The peaks outlined by the dark solid line and the shaded peaks are as defined in the legend for Fig. 1. These results are representative of three experiments.
FIG. 4
FIG. 4
Inhibition of IL-12 receptor upregulation in C3H mice treated with anti-IL-12. Shown is a two-color flow-cytometric analysis of IL-12 binding to LN cells from C3H mice infected 2 days previously that were surface stained for CD4. Control rat IgG and anti-IL-12 antibodies were administered the day before and the day of infection.
FIG. 5
FIG. 5
RPA of IFN-γ mRNA from total LNs of individual C3H mice and BALB/c mice 2 days postinfection with L. major. Representative RPAs for a single C3H mouse and BALB/c mouse are shown on the left and right, respectively. Cyc, cyclophilin. The averages and standard deviations for IFN-γ mRNA quantitation in relative units are shown for one experiment, which included three C3H mice. U, uninfected; I, infected; I IgG, infected plus treatment with control antibody; I αIL-12, infected plus treatment with anti-IL-12 antibodies. These results are representative of three experiments. IFN-γ mRNA quantitation for BALB/c mice is identical to that for C3H mice. U IL-12, uninfected plus treatment with IL-12; I IL-12, infected plus treatment with IL-12. The IFN-γ mRNA relative-unit value for infected mice treated with IL-12 is the average of results for two individual mice. Infection and treatment are described in Materials and Methods.
FIG. 6
FIG. 6
Upregulation of the IL-12 receptor in BALB/c mice treated with anti-IL-4. (A) Anti-IL-4 MAb or control antibody was administered to BALB/c mice the day before and at the time of infection, and LN cells were harvested 2 days later for flow-cytometric analysis like that shown in Fig. 2. (B) A representative RPA of an individual mouse, and IFN-γ mRNA quantitation of total LN cells of three BALB/c mice treated as described for panel A. U, uninfected; I+IgG, infected plus treatment with control IgG; I+αIL-4, infected plus treatment with anti-IL-4 antibodies. Infection and treatment are described in Materials and Methods. The value for infected mice treated with anti-IL-4 antibodies is the average of results for two mice.
FIG. 7
FIG. 7
IL-12 receptor β1 and β2 subunit mRNA expression and IL-12 responsiveness of LN cells during the early immune response to L. major infection in C3H and BALB/c mice. (A) Representative RPA of IL-12Rβ1 and -β2 mRNA from LNs of individual C3H or BALB/c mice 2 days after infection with L. major. The RPA shown is representative of samples from five or six individual mice per group. U, uninfected; I, infected. Also shown are the relative units of β1 or β2 mRNA at 2 days postinfection in C3H and BALB/c mice. Each column shows the means and standard deviations for five or six mice. (B) Lymphocytes isolated from the LNs of C3H or BALB/c mice infected 2 days previously were incubated with IL-12 (1 ng/ml) for 24 h. The supernatants were then harvested, and IFN-γ levels were measured by ELISA to assess IL-12 responsiveness. The results are representative of two experiments with three individual mice each.
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