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

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

doi:10.1172/jci.insight.135143

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.

Highlights

DCs play a central role in priming and polarization of naive CD4+ T cells into subsequent Th subsets [1]
PDCs are a major source of IFN-α for antiviral responses [11], while conventional DCs (cDCs) are classified into XCR1+ could compare MHC-IIhiXCR1+CD11b– dermal DCs (cDC1s) and CD11b+ cDC2 [2, 3]. cDC2s have been further subdivided into ESAMloCD11b+ cDC2 that are dependent on Klf4 transcription and functionally induce Th2 responses [12], while ESAMhiCD11b+ cDC2 are dependent on the Notch2 transcription factor and preferentially induce Th17 responses [13]
Following the i.v. injection of CellTrace Violet–labeled (CTV-labeled) OT-II+Thy1.1+ cells in mice with a Thy1.2 background, OVA-loaded BM-derived DCs (BM-DCs) that were matured with LPS (OVA-LPS/DC) were injected into footpads to induce a Th1 response in the popliteal skin draining lymph node

Summary

Introduction

DCs play a central role in priming and polarization of naive CD4+ T cells into subsequent Th subsets [1]. The CD8+ or CD103+ XCR1+ cDC1 subset is specialized in MHC class I–dependent (MHC-I–dependent) cross-presentation for CD8+ T cell responses [14], as well as in CD4+ Th1 polarization against intracellular pathogens and tumors [10] Under inflammatory conditions, another subset of DCs of monocytic origin (MoDC) is generated that are characterized by expression of macrophage-related markers CD64+CD11b+MAR1+ [15]. The use of BM-DC from IL-12–deficient mice for vaccination against Leishmania infection indicated that the development of Th1 responses relied on an undetermined source of IL-12 production by the recipient mice, not the injected DCs [31] These findings force researchers to question the common belief that injected vaccine MoDCs do provide signals 1, 2, and 3 for Th1 priming. This study shows that DC vaccination requires the bystander activation of endogenous DCs for Th1 priming

Results

Discussion

Methods