Arc/Arg3.1 defines dendritic cells and Langerhans cells with superior migratory ability independent of phenotype and ontogeny in mice

Abstract

The key function of migratory dendritic cells (migDCs) is to take up antigens in peripheral tissues and migrate to draining lymph nodes (dLN) to initiate immune responses. Recently, we discovered that in the mouse immune system activity‐regulated cytoskeleton associated protein/activity‐regulated gene 3.1 (Arc/Arg3.1) is exclusively expressed by migDCs and is a central driver of fast inflammatory migration. However, the frequency of Arc/Arg3.1‐expressing cells in different migDC subsets and Langerhans cells (LCs), their phylogenetic origin, transcription factor dependency, and functional role remain unclear. Here, we found that Arc/Arg3.1+ migDCs derived from common DC precursors and radio‐resistant LCs. We detected Arc/Arg3.1+ migDCs in varying frequencies within each migDC subset and LCs. Consistently, they showed superiority in inflammatory migration. Arc/Arg3.1 expression was independent of the transcription factors Irf4 or Batf3 in vivo. In intradermal Staphylococcus aureus infection that relies on inflammatory antigen transport, Arc/Arg3.1 deletion reduced T‐cell responses. By contrast, Arc/Arg3.1 deficiency did not hamper the immune response to systemic Listeria monocytogenes infection, which does not require antigen transport. Thus, Arc/Arg3.1 expression is independent of ontogeny and phenotype and although it is restricted to a small fraction within each migDC subset and LCs, Arc/Arg3.1+ migDCs are important to facilitate infectious migration.

PD-L1 Reverse Signaling in Dermal Dendritic Cells Promotes Dendritic Cell Migration Required for Skin Immunity

“…Our data examining antigenspecific T cells in response to a pathogen that requires DC migration to the LN support this idea, because we observed reduced antigen-specific CD8 T cells in both Pdl1 À/À and Pdl1 CyMt mice. This defect in response to dermal infection, but not systemic infection, is consistent with what others have observed with loss of dermal DCs (Tintelnot et al, 2019).…”

“…Our data examining antigen-specific T cells in response to a pathogen that requires DC migration to the LN support this idea, because we observed reduced antigen-specific CD8 T cells in both Pdl1 −/− and Pdl1 CyMt mice. This defect in response to dermal infection, but not systemic infection, is consistent with what others have observed with loss of dermal DCs ( Tintelnot et al, 2019 ). Although not evaluated in this study, the migration of Langerhans’s cells, which occurs at later time points compared with migratory cDCs, could be examined to determine whether PD-L1 signaling regulates migration at later points when IFN signaling is decreased.…”

Activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) enhances dendritic cell vaccination in experimental melanoma

“…The differentiation of Arc/ Arg3.1-expressing DCs in vivo was found to be independent of specific transcription factors, suggesting Arc/Arg3.1 as an unequivocal functional marker for DCs with migratory capacity across all DC subsets. 33 These results directed us to the question whether the effect of Arc/Arg3.1 on DC migration may be translatable to immunotherapy for cancer treatment. In this study, we investigated the role of Arc/Arg3.1-dependent DC migration following DC vaccination for its therapeutic efficacy and capability to induce an antigen-specific T cell response in murine experimental melanoma.…”

Effect of pharmacological manipulations on Arc function

“…Arc is also a mediator of inflammatory migratory dendritic cell (migDC) migration from the skin to draining lymph nodes for inflammation-mediated T cell activation. Arc is enriched in four different subsets of migDC as well as Langerhans cells in the skin and draining lymph nodes ( Tintelnot et al., 2019 ). The functional sphingosine 1-phosphate receptor antagonist fingolimod (FTY720), which impairs migDC influx into lymph nodes and is used in the treatment of multiple sclerosis, reduces Arc mRNA in migDC and in draining lymph nodes ( Ufer et al., 2016 ).…”