Using OVA-loaded, matured, gene-modified BM-DC to s.c. vaccinate gene-modified mice, Ashour et al. showed that IL-2+IFNγ+CD4+ Th0 cell priming and expansion required BM-DC migration to draining lymph nodes (dLN)s. The BM-DCs then transferred antigen to endogenous resident MHCIIhiCD103+XCR1+cDC1 and induced them to mature, make IL-12, and present antigen to and polarize Th0 to Th1 cells. Confocal microscopy showed sequential BM-DC/T cell, BM-DC/resident cDC1, cDC1/T cell interactions. RNAseq of matured cDC1 showed reduced expression of genes that inhibit IL-12 and induce Treg/Th2/Th9-cells, and elevation of Th1-promoting genes.
Contributed by Paula Hochman
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.