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. 1999 Oct;104(7):957-65.
doi: 10.1172/JCI7255.

Human major group rhinoviruses downmodulate the accessory function of monocytes by inducing IL-10

J Stöckl  1 , H Vetr, O Majdic, G Zlabinger, E Kuechler, W Knapp
Affiliations

Human major group rhinoviruses downmodulate the accessory function of monocytes by inducing IL-10

J Stöckl et al. J Clin Invest. 1999 Oct.

Abstract

Human rhinoviruses (HRVs) are the predominant cause of the common cold. Although this disease is per se rather harmless, HRV infection is considered to set the stage for more dangerous pathogens in vivo. Here we demonstrate that HRV-14, a member of the major group HRV family, can efficiently inhibit antigen-induced T-cell proliferation and T-cell responses to allogeneic monocytes. HRV-14 triggered a significant downregulation of MHC class II molecules on monocytes. Moreover, supernatants from monocytes cultured in the presence of HRV-14 strongly reduced the allogeneic T-cell stimulatory property of untreated monocytes and monocyte-derived dendritic cells (md-DCs), whereas Epstein Barr virus-transformed B-lymphoblastoid cells were not sensitive. Analysis of the supernatant revealed that HRV-14 induced the production of significant amounts of the immunosuppressive cytokine IL-10. The important T-cell stimulatory cytokine IL-12 or the proinflammatory cytokines IL-1beta or TNF-alpha were not detected or were only minimally detected. Finally, monocytes pretreated with HRV-14 were greatly inhibited in their production of IL-12 upon stimulation with IFN-gamma/LPS. These observations suggest that altered cytokine production in mononuclear phagocytes upon interaction with HRV downmodulates appropriate immune responses during the viral infection.

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Figures

Figure 1
Figure 1
HRV-14 inhibits antigen-specific T-cell proliferation. PBMCs (105) were stimulated with mAb OKT3 (1 μg/mL), SEA or SEB (10 ng/mL), and PPD or tetanus toxoid (1 μg/mL) in the presence (filled bars) or absence (gray bars) of HRV-14 (10 TCID50 per cell). T-cell proliferation was measured on day 3 (for OKT3, SEA, SEB stimulation) and day 5 (for PPD, tetanus toxoid stimulation) of culture by adding (methyl-3H)-TdR followed by measuring thymidine incorporation 18 hours later. Background counts due to ongoing autologous MLR in the absence of specific stimulation were subtracted. The figure shows thymidine uptake, in cpm (mean ± SEM) of 3 independent experiments. Paired Student’s t test was applied for statistical evaluation of data; corresponding P values are indicated.
Figure 2
Figure 2
Inhibition of allogeneic T-cell proliferation by HRV-14. (a) Purified T cells (105) were incubated with graded numbers of allogeneic, purified monocytes in the presence of HRV-14 (10 TCID50 per cell; filled circles), control HeLa cell culture supernatants (open triangles), or medium alone (open circles). Proliferation of T cells was monitored on day 5 of culture by adding (methyl-3H)-TdR followed by measuring thymidine incorporation 18 hours later. The results shown are representative of 5 independent experiments. (b) Pretreatment of HRV-14 with WIN 52035-2 (5 μg/mL) for 30 minutes abolishes the inhibitory effect of HRV-14 (filled triangles). Addition of WIN 52035-2 (5 μg/mL) alone (open triangles) did not influence T-cell proliferation. The results are representative of 2 independent experiments. (c) Dose responses of HRV-14 particles on monocyte-induced allogeneic T-cell proliferation. The figure shows mean values ± SEM of 3 experiments.
Figure 3
Figure 3
Expression of cell-surface molecules on HRV-14–treated monocytes. Purified monocytes were cultured in the presence of HRV-14 (10 TCID50 per cell; gray histograms) or control HeLa cell culture supernatant (thick line) for 2 days. Binding of specific mAb’s was viewed by Oregon-Green–conjugated goat anti-mouse antibodies and analyzed by flow cytometry. The figure shows overlay histogram profiles including the irrelevant control mAb VIAP (dotted line) which are representative of 3 independent experiments.
Figure 4
Figure 4
HRV-14–treated monocytes release an inhibitory factor. Monocytes were cultured for 2 days in the absence or presence of HRV-14 (10 TCID50 per cell). The cell culture supernatants were harvested and examined in the allogeneic T-cell proliferation assay stimulated by irradiated monocytes (a), md-DCs (b), or B-LCLs (c). T-cell proliferative responses in the presence of supernatants of HRV-14–treated monocytes (filled triangles), mock-treated monocytes (open triangles), HRV-14 (filled circles), or medium alone (open circles) were tested in parallel. The figure shows results representative of 4 independent experiments. (d) Dose responses of decreasing amounts of supernatants obtained from HRV-14–treated monocytes were tested in the allogeneic T-cell proliferation assay stimulated by monocytes and md-DCs.
Figure 5
Figure 5
Induction of IL-10 production in monocytes by HRV-14. (a) Supernatants of monocytes (1 × 106/mL) cultured in the presence of HRV-14 (10 TCID50 per cell), LPS (100 ng/mL), or medium for 2 days were analyzed for IL-10, IL-1β, and TNF-α production by ELISA. The figure shows mean values ± SEM of 3 experiments. (b) In separate experiments, detection of cytokine production in monocytes was performed by cytoplasmic staining with specific mAb’s. Monocytes (1 × 106/mL) were cultured for 24 hours in the presence of HRV-14 (10 TCID50 per cell) or LPS (100 ng/mL). After 12 hours of culture, monensin (5 μM) was added in all instances. The cells were harvested, fixed, permeabilized, and subsequently stained with PE-labeled anti–IL-10 mAb. For determination of IL-1β or TNF-α production by cytoplasmic staining, monocytes were incubated with the indicated stimuli for 6 hours in the presence of monensin (5 μM). Cytoplasmic cytokine expression was analyzed by flow cytometry. Overlay histograms show expression in mock-treated cells (open histograms) and monocytes stimulated with HRV-14 (gray histograms) or LPS (open histograms, thick line). The results shown are representative of 3 experiments.
Figure 6
Figure 6
Inhibition of IL-12 production by HRV-14. Purified monocytes (1 × 106/mL) were cultured for 2 days in the absence or presence of HRV-14 (10 TCID50 per cell) or LPS (100 ng/mL) with or without prestimulation with IFN-γ (300 U/mL) for 24 hours. Supernatants of cultured monocytes were analyzed for IL-12 p70 release by ELISA (a). The figure shows mean values ± SEM of 3 experiments. (b) Cytoplasmic staining of monocytes with PE-conjugated anti-IL-12 mAb or anti-IL-6 mAb. Monocytes were stimulated as follows: mock stimulated (A); +IFN-γ/LPS (B and G); +HRV-14/IFN-γ/LPS (C and H); +HRV-14/anti–IL-10 antibody/IFN-γ/LPS (D); +IL-10 (5 ng/mL)/IFN-γ/LPS (E); and +IL-10/anti–IL-10 antibody/IFN-γ/LPS (F).
Figure 7
Figure 7
Neutralization of IL-10 abolishes the inhibitory effect of HRV-14. Purified T cells (105) were incubated with graded numbers of allogeneic, purified monocytes in the absence (open circles) or presence of supernatants from HRV-14–treated monocytes that had been pretreated with (filled triangles) or without (filled squares) neutralizing anti–IL-10 antibodies.
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