IL-12 from endogenous cDC1, and not vaccine DC, is required for Th1 induction
DiyaaElDin Ashour, Panagiota Arampatzi, Vladimir Pavlovic, Konrad U. Förstner, Tsuneyasu Kaisho, Andreas Beilhack, Florian Erhard, Manfred B. Lutz
DiyaaElDin Ashour, Panagiota Arampatzi, Vladimir Pavlovic, Konrad U. Förstner, Tsuneyasu Kaisho, Andreas Beilhack, Florian Erhard, Manfred B. Lutz
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Research Article Immunology Vaccines

IL-12 from endogenous cDC1, and not vaccine DC, is required for Th1 induction

Abstract

Success of DC vaccines relies on the quality of antigen presentation, costimulation, lymph node migration, and the release of IL-12, in case of Th1 priming. Here, we provide evidence for interaction between the injected vaccine DCs with endogenous lymph node–resident DCs for Th1 induction. While migration of the injected DCs was essential for antigen delivery to the lymph node, the injected DCs contributed only partially to Th0 priming and were unable to instruct Th1 generation. Instead, we provide evidence that the lymph node–resident XCR1+ DCs are activated by the injected DCs to present the cognate antigen and release IL-12 for Th1 polarization. The timing of interactions in the draining lymph nodes appeared step-wise as (a) injected DCs with cognate T cells, (b) injected DCs with bystander DCs, and (c) bystander DCs with T cells. The transcriptome of the bystander DCs showed a downregulation of Treg- and Th2/Th9-inducing genes and self-antigen presentation, as well as upregulation of MHC class II and genes required for Th1 instruction. Together, these data show that injected mature lymph node migratory DCs direct T cell priming and bystander DC activation, but not Th1 polarization, which is mediated by endogenous IL-12p70+XCR1+ resident bystander DCs. Our results are of importance for clinical DC-based vaccinations against tumors where endogenous DCs may be functionally impaired by chemotherapy.

Authors

DiyaaElDin Ashour, Panagiota Arampatzi, Vladimir Pavlovic, Konrad U. Förstner, Tsuneyasu Kaisho, Andreas Beilhack, Florian Erhard, Manfred B. Lutz

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Figure 3

Endogenous CD103+XCR1+ resident DCs are required for antigen presentation and Th1 polarization.

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Endogenous CD103+XCR1+ resident DCs are required for antigen presentatio...
(A) Graphs comparing lymph node cell counts, frequency of injected OT-II+Thy1.1+CD4+ T cells, and percentage of the cytokine-producing cells after s.c. injection of Il12a–/– OVA-LPS/DC into WT mice (blue bars), Il12a–/– OVA-LPS/DC into Ccr7–/– recipient mice (red bars), Il12a–/– OVA-LPS/DC into Il12a–/–Ccr7–/– mice (white bars), or WT.OVA-LPS/DC into MHC-II–/– (turquoise bars) recipient mice compared with T cell injection alone (black bars). (B) Graphs comparing lymph node cell counts, frequency of injected OT-II+Thy1.1+CD4+ T cells, and percentage of the cytokine-producing cells after s.c. injection of WT.OVA-LPS/DC into WT recipient mice (gray bar) or Il12a–/– OVA-LPS/DC into XCR1-DTR-Venus recipient mice (yellow bars) compared with T cell injection alone (black bars). Data are representative of 2 independent experiments analyzing at least 5 mice per group. One-way ANOVA with multiple comparisons and Tukey’s post hoc test; *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001.