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. 2021 Mar 18;9(3):277.
doi: 10.3390/vaccines9030277.

Decrease of IL-5 Production by Naive T Cells Cocultured with IL-18-Producing BCG-Pulsed Dendritic Cells from Patients Allergic to House Dust Mite

Magdalena Kowalewicz-Kulbat  1 , Piotr Szpakowski  1   2 , Krzysztof T Krawczyk  1 , Marek L Kowalski  3 , Slawomir Kosinski  4 , Franck Biet  5 , Wieslawa Rudnicka  1 , Camille Locht  1   6
Affiliations

Decrease of IL-5 Production by Naive T Cells Cocultured with IL-18-Producing BCG-Pulsed Dendritic Cells from Patients Allergic to House Dust Mite

Magdalena Kowalewicz-Kulbat et al. Vaccines (Basel). .

Abstract

The only currently available anti-tuberculosis vaccine, Bacillus Calmette-Guérin (BCG), has been reported to also protect against unrelated diseases, including inflammatory diseases such as allergic asthma. Recombinant BCG strains that produce IL-18 have been shown to enhance Th1 responses over non-recombinant BCG and to reduce IL-5 production and bronchoalveolar eosinophilia in mice. However, their ability to decrease the immune polarization of human Th2 cells is not known. Here, we show that BCG and recombinant BCG producing human IL-18 (rBCG-hIL-18) induced the maturation of Der p 1-stimulated monocyte-derived dendritic cells (MD-DCs) from healthy controls and from patients allergic to house dust mites. After incubation with mycobacteria and Der p 1, MD-DCs produced significantly more IL-23 and IP-10 but had no effect on IL-12p70 or IL-10 production compared to Der p 1-pulsed MD-DCs in the absence of mycobacteria. In the presence of Der p 1, BCG- and rBCG-hIL-18-pulsed MD-DCs cocultured with naive, but not with memory T cells from allergic patients, resulted in a decrease in IL-5 production compared to non-pulsed MD-DCs cultured in the presence of Der p 1. BCG, and especially rBCG-hIL-18, may thus be potential therapeutic tools to reduce exacerbated Th2 responses in patients with allergic asthma.

Keywords: BCG; Der p 1; Th1/Th2 cells; asthma; dendritic cells; rBCG-hIL-18.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CD86 (a), DC-SIGN (b) and CD40 (c) surface expression on MD-DCs from healthy donors and allergic patients. Human MD-DCs were stimulated either with BCG (1:1), rBCG-hIL-18 (rBCG) (1:1), Der p 1 (1 μg/mL), Derp1/BCG or Der p 1/rBCG-hIL-18 for 24 h or were left unstimulated (DC). Box plots represent the median MFI and interquartile range values for 22 allergic donors and 40 healthy donors. Fluorescence intensity was calculated by the MFI (once for each donor) of the receptor expression from which the MFI obtained with an isotype-matched antibody was subtracted. Statistical analyses were performed by using the Kruskal–Wallis non-parametric test. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001; versus control (unstimulated DC), unless indicated by the horizontal bars; Δ p < 0.05; ΔΔ p < 0.01 versus Der p 1.
Figure 2
Figure 2
IL-23 (a), IL-10 (b) and IP-10 (c) production by stimulated MD-DCs from allergic patients and healthy donors. Human MD-DCs were stimulated with BCG (1:1), rBCG-hIL-18 (rBCG) (1:1), Der p 1 (1 μg/mL), Der p 1/BCG or Der p 1/rBCG for 24 h or were left unstimulated (DC). The cytokine (IL-23, IL-10) and chemokine (IP-10) levels in culture supernatants were measured in duplicate by ELISA. Data shown represent the medians ± SEM for 22 allergic patients and 40 healthy donors. Statistical analyses were performed by using the Mann–Whitney U test for unpaired data. * p < 0.05; ** p < 0.01; *** p < 0.001 versus control (unstimulated DC), unless indicated by the horizontal bars, Δ p < 0.05; ΔΔ p < 0.01; ΔΔΔ p < 0.001 versus Der p 1.
Figure 3
Figure 3
Secretion of IFN-γ by human naive T cells (a) and memory T cells (b) following 96 h coculture with BCG- (1:1), rBCG-hIL-18 (rBCG)- (1:1), Der p 1- (1 μg/mL), Der p 1/BCG- or Der p 1/rBCG-pulsed autologous MD-DCs (ratio MD-DCs/T cells, 1:10). The cytokine levels in the cocultures were measured in duplicate by ELISA. Data shown are the medians ± SEM for 22 allergic patients and 40 healthy donors. Statistical analyses were performed by using the Kruskal–Wallis test for unpaired data. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 versus control (unstimulated DC), unless indicated by the horizontal bars; Δ p < 0.05; ΔΔΔΔ p < 0.0001 versus Der p 1.
Figure 4
Figure 4
Secretion of IL-5 by human naive T cells (a) and memory T cells (b) following 96 h coculture with BCG- (1:1), rBCG-hIL-18 (rBCG)- (1:1), Der p 1- (1 μg/mL), Der p 1/BCG- or Der p 1/rBCG-pulsed autologous MD-DCs (ratio MD-DCs/T cells, 1:10). The cytokine levels in the cocultures were measured in duplicate by ELISA. Data shown are the medians ± SEM for 22 allergic patients and 40 healthy donors. Statistical analyses were performed by using the Kruskal–Wallis test for unpaired data. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 versus control (unstimulated DC), unless indicated by the horizontal bars; Δ p < 0.05 versus Der p 1.
Figure 5
Figure 5
Secretion of IL-10 by human naive T cells (a) and memory T cells (b) following 96 h coculture with BCG- (1:1), rBCG-hIL-18 (rBCG)- (1:1), Der p 1- (1 μg/mL), Der p 1/BCG- or Der p 1/rBCG-pulsed autologous MD-DCs (ratio MD-DCs/T cells, 1:10). The cytokine levels in the cocultures were measured in duplicate by ELISA. Data shown are the medians ± SEM for 22 allergic patients and 40 healthy donors. Statistical analyses were performed by using the Kruskal–Wallis test for unpaired data. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001 versus control (unstimulated DC), unless indicated by the horizontal bars; ΔΔΔ p < 0.001 versus Der p 1.
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