0000000000372294
AUTHOR
Felix Melchior
Dermal CD207-Negative Migratory Dendritic Cells Are Fully Competent to Prime Protective, Skin Homing Cytotoxic T-Lymphocyte Responses
Dendritic cells (DCs) are important inducers and regulators of T-cell responses. They are able to activate and modulate the differentiation of CD4+ and CD8+ T cells. In the skin, there are at least five phenotypically distinct DC subpopulations that can be distinguished by differential expression of the cell surface markers CD207, CD103, and CD11b. Previous studies have suggested that dermal CD11b−CD207+ conventional type 1 DCs are indispensable for the priming of a skin homing cytotoxic T-lymphocyte response. However, conventional type 1 DCs are also the only skin DC subset capable of cross-presenting exogenous antigens on major histocompatibility complex class I. Thus, it remained unclear…
Microbiota-Induced Type I Interferons Instruct a Poised Basal State of Dendritic Cells
Summary Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are not well understood. Here, we report that the indigenous microbiota controls constitutive production of type I interferons (IFN-I) by plasmacytoid DCs. Using genome-wide analysis of transcriptional and epigenetic regulomes of cDCs from germ-free and IFN-I receptor (IFNAR)-deficient mice, we found that tonic IFNAR signaling instructs a spec…
Production of Extracellular Adenosine by CD73+ Dendritic Cells Is Crucial for Induction of Tolerance in Contact Hypersensitivity Reactions
Dendritic cells (DCs) express the ecto-5′-nucleotidase CD73 that generates immunosuppressive adenosine (Ado) by dephosphorylation of extracellular Ado monophosphate and diphosphate. To investigate whether CD73-derived Ado has immune-suppressive activity, 2,4-dinitrothiocyanobenzene (DNTB) was applied to skin of wild-type (WT) or CD73-deficient (CD73–/–) mice, followed by sensitization and challenge with 2,4-dinitrofluorobenzene. In this model, we show the induction of tolerance by DNTB against 2,4-dinitrofluorobenzene only in WT but not in CD73–/– mice. Analysis of skin DCs showed increased expression of CD73 after application of DNTB in WT mice. That was accompanied by elevated concentrati…
Intervention of Inflammatory Monocyte Activity Limits Dermal Fibrosis
Monocytes and monocyte-derived cells are important players in the initiation, progression, and resolution of inflammatory skin reactions. As inflammation is a prerequisite for fibrosis development, we focused on the role of monocytes in cutaneous fibrosis, the clinical hallmark of patients suffering from systemic sclerosis. Investigating the function of monocytes in reactive oxygen species–induced dermal fibrosis, we observed that early monocyte depletion partially reduced disease severity. Low numbers of inflammatory Ly6Chigh monocytes, as well as inhibition of CCR2 and CCL2 in wild type animals by a specific L-RNA aptamer, mitigated disease parameters, indicating a pivotal role for CCR2+ …