ABSTRACT
Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⺠CLEC9A⺠DCs and CD1c⺠DCs are murine CD103⺠DCs and CD64⻠CD11b⺠DCs. In addition, human tissues also contain CD14⺠cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⺠cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14⺠monocytes and dermal CD14⺠cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⺠cells are CD11b⺠CD64⺠monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system.
Subject(s)
Lipopolysaccharide Receptors/metabolism , Macrophages/immunology , Skin/immunology , Animals , CD11b Antigen/biosynthesis , Cell Differentiation/immunology , Cell Lineage/immunology , Cell Movement/immunology , Cells, Cultured , Dendritic Cells/immunology , Female , Humans , Immunologic Memory/immunology , Mice , Mice, Transgenic , Receptors, IgG/biosynthesis , Skin/cytology , T-Lymphocytes/immunologyABSTRACT
Mouse and human dendritic cells (DCs) are composed of functionally specialized subsets, but precise interspecies correlation is currently incomplete. Here, we showed that murine lung and gut lamina propria CD11b+ DC populations were comprised of two subsets: FLT3- and IRF4-dependent CD24(+)CD64(-) DCs and contaminating CSF-1R-dependent CD24(-)CD64(+) macrophages. Functionally, loss of CD24(+)CD11b(+) DCs abrogated CD4+ T cell-mediated interleukin-17 (IL-17) production in steady state and after Aspergillus fumigatus challenge. Human CD1c+ DCs, the equivalent of murine CD24(+)CD11b(+) DCs, also expressed IRF4, secreted IL-23, and promoted T helper 17 cell responses. Our data revealed heterogeneity in the mouse CD11b+ DC compartment and identifed mucosal tissues IRF4-expressing DCs specialized in instructing IL-17 responses in both mouse and human. The demonstration of mouse and human DC subsets specialized in driving IL-17 responses highlights the conservation of key immune functions across species and will facilitate the translation of mouse in vivo findings to advance DC-based clinical therapies.
Subject(s)
Aspergillus fumigatus/immunology , Dendritic Cells/metabolism , Interferon Regulatory Factors/metabolism , Interleukin-17/metabolism , Th17 Cells/metabolism , Animals , CD11b Antigen/metabolism , CD24 Antigen/metabolism , Cell Differentiation/immunology , Dendritic Cells/immunology , Humans , Interleukin-17/biosynthesis , Interleukin-23/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/immunology , Macrophages/metabolism , Mice , Receptors, IgG/metabolism , Respiratory Mucosa/cytology , Respiratory Mucosa/immunology , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
Dendritic cell (DC)-mediated cross-presentation of exogenous antigens acquired in the periphery is critical for the initiation of CD8(+) T cell responses. Several DC subsets are described in human tissues but migratory cross-presenting DCs have not been isolated, despite their potential importance in immunity to pathogens, vaccines, and tumors and tolerance to self. Here, we identified a CD141(hi) DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c(+) and CD14(+) tissue DCs and superior at cross-presenting soluble antigens. Cutaneous CD141(hi) DCs were closely related to blood CD141(+) DCs, and migratory counterparts were found among skin-draining lymph node DCs. Comparative transcriptomic analysis with mouse showed tissue DC subsets to be conserved between species and permitted close alignment of human and mouse DC subsets. These studies inform the rational design of targeted immunotherapies and facilitate translation of mouse functional DC biology to the human setting.
Subject(s)
Antigens, CD/metabolism , Cross-Priming/immunology , Dendritic Cells/immunology , Dendritic Cells/metabolism , Integrin alpha Chains/metabolism , Animals , Antigens/immunology , Cell Movement/immunology , Chemokine CXCL10/biosynthesis , Gene Expression Profiling , Humans , Immunophenotyping , Langerhans Cells/immunology , Langerhans Cells/metabolism , Lymph Nodes/immunology , Lymph Nodes/metabolism , Mice , Skin/immunology , Transcriptome , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
AIMS: Brugada syndrome (BrS) is a rare heritable ventricular arrhythmia. Genetic defects in SCN5A, a gene that encodes the α-subunit of the sodium ion channel Nav1.5, are present in 15-30% of BrS cases. SCN5A remains by far, the highest yielding gene for BrS. We studied a young male who presented with syncope at age 11. This proband was screened for possible disease causing SCN5A mutations. The inheritance pattern was also examined amongst his first-degree family members. METHODS AND RESULTS: The proband had a baseline electrocardiogram that showed Type 2 BrS changes, which escalated to a characteristic Type I BrS pattern during a treadmill test before polymorphic ventricular tachycardia onset at a cycle length of 250 ms. Mutational analysis across all 29 exons in SCN5A of the proband and first-degree relatives of the family revealed that the proband inherited a compound heterozygote mutation in SCN5A, specifically p.A226V and p.R1629X from each parent. To further elucidate the functional changes arising through these mutations, patch-clamp electrophysiology was performed in TSA201 cells expressing the mutated SCN5A channels. The p.A226V mutation significantly reduced peak sodium current (INa) to 24% of wild type (WT) whereas the p.R1629X mutation abolished the current. To mimic the functional state in our proband, functional expression of the compound variants A226V + R1629X resulted in overall peak INa of only 13% of WT (P < 0.01). CONCLUSION: Our study is the first to report a SCN5A compound heterozygote in a Singaporean Chinese family. Only the proband carrying both mutations displayed the BrS phenotype, thus providing insights into the expression and penetrance of BrS in an Asian setting.